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Hyaluronan and synovial joint: function, distribution and healing

Hyaluronan and synovial joint: function, distribution and healing Interdiscip Toxicol. 2013; Vol. 6(3): 111–125. interdisciplinary doi: 10.2478/intox-2013-0019 Published online in: www.intertox.sav.sk & www.versita.com/it Copyright © 2013 SETOX & IEPT, SASc. This is an Open Access article distributed under the terms of the Creative Commons Attribu- tion License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. REVIEW ARTICLE Hyaluronan and synovial joint: function, distribution and healing 1,2 Tamer Mahmoud TAMER Polymer Materials Research Department, Advanced Technologies and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, Egypt Laboratory of Bioorganic Chemistry of Drugs, Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, Bratislava, Slovak Republic ITX060313R03 • Received: 18 July 2013 • Revised: 25 August 2013 • Accepted: 10 September 2013 ABSTRACT Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of hyaluronan causing several diseases related to joints. This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for using thiol compounds as antioxidants preventing HA degradations under inflammation conditions. KEY WORDS: synovial joint fluid; hyaluronan; antioxidant; thiol compound Introduction The human skeleton consists of both fused and individual Cartilage functions also as a shock absorber. This bones supported and supplemented by ligaments, tendons, property is derived from its high water entrapping capac- and skeletal muscles. Articular ligaments and tendons are ity as well as from the structure and intermolecular inter- the main parts holding together the joint(s). In respect of actions among polymeric components that constitute the movement, there are freely moveable, partially moveable, and immovable joints. Synovial joints (Figure 1), the freely moveable ones, allow for a large range of motion Synovium and encompass wrists, knees, ankles, shoulders, and hips Cartilage (Kogan, 2010). Structure of synovial joints Cartilage In a healthy synovial joint, heads of the bones are encased in a smooth (hyaline) cartilage layer. These tough slippery layers – e.g. those covering the bone ends in the knee joint – belong to mechanically highly stressed tissues in the human body. At walking, running, or sprinting the strokes frequency attain approximately 0.5, 2.5 or up to 10 Hz. Joint cavity with Ligament forming Correspondence address: synovial fluid joint capsule Dr. Tamer Mahmoud Tamer Polymer Materials Research Department, Advanced Technologies and New Materials Research Institute (ATNMRI), City of Scientific Research Figure 1. Normal, healthy synovial joint (adapted from Kogan, and Technological Applications (SRTA- City) 2010). New Borg El-Arab City 21934, Alexandria, Egypt. E-MAIL: ttamer85@gmail.com Hyaluronan and synovial joint Tamer Mahmoud Tamer cartilage tissue (Servaty et al., 2000). Figure 2 sketches pool through which nutrients and regulatory cytokines a section of the cartilage – a chondrocyte cell that per- traverse. SF contains molecules that provide low-friction manently restructures/rebuilds its extracellular matrix. and low-wear properties to articulating cartilage surfaces. Three classes of proteins exist in articular cartilage: col- Molecules postulated to play a key role in lubrication lagens (mostly type II collagen); proteoglycans (primarily alone or in combination, are proteoglycan 4 (PRG4) aggrecan); and other noncollagenous proteins (including (Swann et al., 1985) present in SF at a concentration of link protein, fibronectin, COMP – cartilage oligomeric 0.05–0.35 mg/ml (Schmid et al., 2001), hyaluronan (HA) matrix protein) and the smaller proteoglycans (biglycan, (Ogston & Stanier, 1953) at 1–4 mg/ml (Mazzucco et al., decorin, and fibromodulin). The interaction between 2004), and surface-active phospholipids (SAPL) (Schwarz highly negatively charged cartilage proteoglycans and & Hills, 1998) at 0.1 mg/ml (Mazzucco et al., 2004). type II collagen fibrils is responsible for the compressive Synoviocytes secrete PRG4 (Jay et al., 2000; Schumacher and tensile strength of the tissue, which resists applied et al., 1999) and are the major source of SAPL (Dobbie load in vivo. et al., 1995; Hills & Crawford, 2003; Schwarz & Hills, 1996), as well as HA (Haubeck et al., 1995; Momberger et Synovium/synovial membrane al., 2005) in SF. Other cells also secrete PRG4, including Each synovial joint is surrounded by a fibrous, highly vas- chondrocytes in the superficial layer of articular cartilage cular capsule/envelope called synovium, whose internal (Schmid et al., 2001b; Schumacher et al., 1994) and, to a surface layer is lined with a synovial membrane. Inside much lesser extent, cells in the meniscus (Schumacher et this membrane, type B synoviocytes (fibroblast-like cell al., 2005). lines) are localized/embedded. Their primary function is As a biochemical depot, SF is an ultra filtrate of blood to continuously extrude high-molar-mass hyaluronans plasma that is concentrated by virtue of its filtration (HAs) into synovial f luid. through the synovial membrane. The synovium is a thin lining (~50 μm in humans) comprised of tissue macro- Synovial fl uid phage A cells, fibroblast-like B cells (Athanasou & Quinn, The synovial fluid (SF) of natural joints normally func- 1991; Revell, 1989; Wilkinson et al., 1992), and fenes- tions as a biological lubricant as well as a biochemical trated capillaries (Knight & Levick, 1984). It is backed Link protein Aggrecan Hyaluronan Fibronectin Integrin COMP Biglycan Chondrocyte Decorin Type IX collagen Fibromodulin Type II collagen Figure 2. Articular cartilage main components and structure (adapted from Chen et al., 2006). ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) S–S Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central by a thicker layer (~100 μm) of loose connective tissue called the subsynovium (SUB) that includes an extensive NORMAL JOINT system of lymphatics for clearance of transported mol- Cartilage Tendon ecules. The cells in the synovium form a discontinuous Muscle layer separated by intercellular gaps of several microns in width (Knight & Levick, 1984; McDonald & Levick, 1988). The extracellular matrix in these gaps contains collagen types I, III, and V (Ashhurst et al., 1991; Rittig et al., 1992), hyaluronan (Worrall et al., 1991), chondroitin sulphate (Price et al., 1996; Worrall et al., 1994), biglycan and decorin proteoglycans (Coleman et al., 1998), and fibronectin (Poli et al., 2004). The synovial matrix pro- vides the permeable pathway through which exchange of molecules occurs (Levick, 1994), but also offers sufficient outflow resistance (Coleman et al., 1998; Scott et al., Synovium 1998) to retain large solutes of SF within the joint cavity. Joint Capsule Together, the appropriate ref lection of secreted lubricants Bone by the synovial membrane and the appropriate lubricant Synovial Fluid secretion by cells are necessary for development of a mechanically functional SF (Blewis et al., 2007). In the joint, HA plays an important role in the protec- tion of articular cartilage and the transport of nutrients to cartilage. In patients with rheumatoid arthritis (RA), Bone (Figure 3) it has been reported that HA acts as an anti JOINT AFFECTED BY inflammatory substance by inhibiting the adherence of RHEUMATOID ARTHRITIS immune complexes to neutrophils through the Fc receptor (Brandt, 1970), or by protecting the synovial tissues from Bone Loss/Erosion the attachment of inflammatory mediators (Miyazaki et al., 1983, Mendichi & Soltes, 2002). Cartilage Loss •– • Reactive oxygen species (ROS) (O , H O , OH) are 2 2 2 generated in abundance by synovial neutrophils from RA patients, as compared with synovial neutrophils of osteo- arthritis (OA) patients and peripheral neutrophils of both RA and OA patients (Niwa et al., 1983). McCord (1973) demonstrated that HA was susceptible to degradation by ROS in vitro, and that this could be protected by superoxide dismutase (SOD) and/or catalase, which suggests the possibility that there is pathologic oxidative damage to synovial fluid components in RA patients. Dahl et al. (1985) reported that there are reduced HA concentrations in synovial fluids from RA patients. It has also been reported that ROS scavengers inhibit the Inflamed Synovium degradation of HA by ROS (Soltes, 2010; Blake et al., 1981; Bone Loss Betts & Cleland, 1982; Soltes et al., 2004). (Generalized) Swollen Joint Capsule These findings appear to support the hypothesis that ROS are responsible for the accelerated degradation of HA in the rheumatoid joint. In the study of Juranek and Soltes (2012) the oxygen radical scavenging activities of synovial Figure 3. Normal, (healthy) and rheumatoid arthritis synovial joint. fluids from both RA and OA patients were assessed, and the antioxidant activities of these synovial fluids were analyzed by separately examining HA, d-glucuronic acid, and N-acetyl-d-glucosamine. contained two sugar molecules, one of which was uronic acid. For convenience, therefore, they proposed the name “hyaluronic acid”. The popular name is derived from Hyaluronan “hyalos”, which is the Greek word for glass + uronic acid (Meyer & Palmer, 1934). At the time, they did not know In 1934, Karl Meyer and his colleague John Palmer iso- that the substance which they had discovered would lated a previously unknown chemical substance from the prove to be one of the most interesting and useful natural vitreous body of cows’ eyes. They found that the substance macromolecules. HA was first used com mercially in 1942 Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer when Endre Balazs applied for a patent to use it as a substi- that hyaluronan separates most tissue surfaces that slide tute for egg white in bakery products (Necas et al., 2008). along each other. The extremely lubricious properties The term “hyaluronan” was introduced in 1986 to con- of hyaluronan have been shown to reduce postoperative form to the international nomenclature of polysaccharides adhesion forma tion following abdominal and orthopedic and is attributed to Endre Balazs (Balazs et al., 1986) who surgery. As mentioned, the polymer in solution assumes coined it to encompass the different forms the molecule a stiffened helical configuration, which can be at tributed can take, e.g, the acid form, hyaluronic acid, and the salts, to hydrogen bonding between the hydroxyl groups along such as sodium hyaluronate, which forms at physiological the chain. As a result, a coil structure is formed that traps pH (Laurent, 1989). HA was subsequently isolated from approximately 1000 times its weight in water (Chabrecek et many other sources and the physicochemi cal structure al., 1990; Cowman & Matsuoka, 2005; Schiller et al., 2011) properties and biological role of this polysaccharide were studied in numerous laborato ries (Kreil, 1995). This work has been summarized in a Ciba Foundation Symposium Properties of hyaluronan (Laurent, 1989) and a recent review (Laurent & Fraser, 1992; Chabrecek et al., 1990; Orvisky et al., 1992). Hyaluronan networks Hyaluronan (Figure 4) is a unique biopolymer com- The physico-chemical properties of hyaluronan were stud- posed of repeating disaccharide units formed by N-acetyl- ied in detail from 1950 onwards (Comper & Laurent, 1978). d-glucosamine and d-glucuronic acid. Both sugars are The molecules behave in solution as highly hydrated spatially related to glucose which in the β-configuration randomly kinked coils, which start to entangle at concen- allows all of its bulky groups (the hydroxyls, the carbox- trations of less than 1 mg/mL. The entanglement point ylate moiety, and the anomeric carbon on the adjacent can be seen both by sedimentation analysis (Laurent et sugar) to be in sterically favorable equatorial posi tions al., 1960) and viscosity (Morris et al., 1980). More recently while all of the small hydrogen atoms occupy the less Scott and his group have given evidence that the chains sterically favorable axial positions. Thus, the structure of when entangling also interact with each other and form the disaccharide is energetically very stable. HA is also stretches of double helices so that the network becomes unique in its size, reaching up to several million Daltons mechanically more firm (Scott et al., 1991). and is synthesized at the plasma membrane rather than in the Golgi, where sulfated glycosaminoglycans are added Rheological properties to protein cores (Itano & Kimata, 2002; Weigel et al., 1997; Solutions of hyaluronan are viscoelastic and the viscosity Kogan et al., 2007a). is markedly shearing dependent (Morris et al., 1980; Gibbs In a physiological solution, the backbone of a HA mol- et al., 1968). Above the entanglement point the viscosity ecule is stiffened by a combina tion of the chemical struc- increases rapidly and exponentially with concentration 3.3 ture of the disaccha ride, internal hydrogen bonds, and (~c ) (Morris et al., 1980) and a solution of 10 g/l may interactions with the solvent. The axial hydrogen atoms have a viscosity at low shear of ~10 times the viscosity of form a non-polar, relatively hydrophobic face while the the solvent. At high shear the viscosity may drop as much equatorial side chains form a more polar, hy drophilic face, as ~10 times (Gibbs et al., 1968). The elasticity of the thereby creating a twisting ribbon structure. Solutions of system increases with increasing molecular weight and hyaluronan manifest very unusual rheological properties concentration of hyaluronan as expected for a molecular and are exceedingly lubricious and very hydrophilic. In network. The rheological properties of hyaluronan have solution, the hyaluronan polymer chain takes on the been connected with lubrication of joints and tissues form of an expanded, random coil. These chains entangle and hyaluronan is commonly found in the body between with each other at very low concentrations, which may surfaces that move along each other, for example cartilage contribute to the unusual rheological proper ties. At surfaces and muscle bundles (Bothner & Wik, 1987). higher concentrations, solutions have an extremely high but shear-dependent viscosity. A 1% solution is like jelly, Water homeostasis but when it is put under pressure it moves easily and A fixed polysaccharide network offers a high resistance can be administered through a small-bore needle. It has to bulk flow of solvent (Comper & Laurent, 1978). This therefore been called a “pseudo-plastic” material. The was demonstrated by Day (1950) who showed that hyal- extraordi nary rheological properties of hyaluronan solu- uronidase treatment removes a strong hindrance to water f low through a fascia. Thus HA and other polysaccharides tions make them ideal as lubricants. There is evidence prevent excessive fluid fluxes through tissue compart- ments. Furthermore, the osmotic pressure of a hyaluronan O H C H O C O H 3 solution is non-ideal and increases exponentially with the O H N H O C H O H O O concentration. In spite of the high molecular weight of O O H O H O n N H O C O H the polymer the osmotic pressure of a 10 g/l hyaluronan C H O C O H 3 O H solution is of the same order as an l0 g/l albumin solu- tion. The exponential relationship makes hyaluronan Figure 4. Structural formula of hyaluronan – the acid form. and other polysaccharides excellent osmotic buffering substances – moderate changes in concentration lead ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central to marked changes in osmotic pressure. Flow resistance Medical applications of hyaluronic acid together with osmotic buffering makes hyaluronan an The viscoelastic matrix of HA can act as a strong bio- ideal regulator of the water homeostasis in the body. compatible support material and is therefore commonly used as growth scaffold in surgery, wound healing and Network interactions with other macromolecules embryology. In addition, administration of purified high The hyaluronan network retards the diffusion of other molecular weight HA into orthopaedic joints can restore molecules (Comper & Laurent, 1978; Simkovic et al., the desirable rheological properties and alleviate some of 2000). It can be shown that it is the steric hindrance which the symptoms of osteoarthritis (Balazs & Denlinger, 1993; restricts the movements and not the viscosity of the solu- Balazs & Denlinger, 1989; Kogan et al., 2007). The success tion. The larger the molecule the more it will be hindered. of the medical applications of HA has led to the produc- In vivo hyaluronan will therefore act as a diffusion barrier tion of several successful commercial products, which and regulate the transport of other substances through have been extensively reviewed previously. the intercellular spaces. Furthermore, the network will Table 1 summarizes both the medical applications and exclude a certain volume of solvent for other molecules; the commonly used commercial preparations containing the larger the molecule the less space will be available HA used within this field. HA has also been extensively to it (Comper & Laurent, 1978). A solution of 10 g/l of studied in ophthalmic, nasal and parenteral drug delivery. hyaluronan will exclude about half of the solvent to serum In addition, more novel applications including pulmonary, albumin. Hyaluronan and other polysaccharides therefore implantation and gene delivery have also been suggested. take part in the partition of plasma proteins between the Generally, HA is thought to act as either a mucoadhesive vascular and extravascular spaces. The excluded volume and retain the drug at its site of action/absorption or to phenomenon will also affect the solubility of other macro- modif y the in vivo release/absorption rate of the therapeu- molecules in the interstitium, change chemical equilibria tic agent. A summary of the drug delivery applications of and stabilize the structure of, for example, collagen fibers. HA is shown in Table 2. Table 1. Summary of the medical applications of hyaluronic acid (Brown & Jones, 2005). Disease state Applications Commercial products Publications Hochburg, 2000; Altman, 2000; Dougados, 2000; Guidolin et al., Hyalgan® (Fidia, Italy) 2001; Maheu et al., 2002; Barrett & Siviero, 2002; Miltner et al., Lubrication and mechanical Artz® (Seikagaku, Japan) 2002;Tascioglu and Oner, 2003; Uthman et al., 2003; Kelly et al., Osteoarthritis support for the joints ORTHOVISC® (Anika, USA) 2003; Hamburger et al., 2003; Kirwan, 2001; Ghosh & Guidolin, Healon®, Opegan® and Opelead® 2002; Mabuchi et al., 1999; Balazs, 2003; Fraser et al., 1993; Zhu & Granick, 2003. Ghosh & Jassal, 2002; Risbert, 1997; Inoue & Katakami, 1993; Implantation of artificial Surgery and Bionect®, Connettivina® Miyazaki et al., 1996; Stiebel-Kalish et al., 1998; Tani et al., 2002; intraocular lens, wound healing and Jossalind® Vazquez et al., 2003; Soldati et al., 1999; Ortonne, 1996; Cantor et viscoelastic gel al., 1998; Turino & Cantor, 2003. Simon et al., 2003; Gardner et al., 1999; Vanos et al., 1991; Kem- mann, 1998; Suchanek et al., 1994; Joly et al., 1992; Gardner, 2003; Culture media for the use of Embryo implantation EmbryoGlue® (Vitrolife, USA) Lane et al., 2003; Figueiredo et al., 2002, Miyano et al., 1994; Kano in vitro fertilization et al., 1998; Abeydeera, 2002; Jaakma et al., 1997; Furnus et al., 1998;Jang et al., 2003. Table 2. Summary of the drug delivery applications of hyaluronic acid. Route Justification Therapeutic agents Publications Jarvinen et al., 1995; Sasaki et al., 1996; Gurny et al., 1987; Camber et al., 1987; Camber & Edman, 1989; Increased ocular residence of drug, Pilocarpine, tropicamide, timolol, gen- Saettone et al., 1994; Saettone et al., 1991; Bucolo et al., 1998; Ophthalmic which can lead to increased timycin, tobramycin, Bucolo & Mangiafico, 1999; Herrero-Vanrell et al., 2000; Moreira bioavailability arecaidine polyester, (S) aceclidine et al., 1991; Bernatchez et al., 1993; Gandolfi et al., 1992; Langer et al., 1997. Bioadhesion resulting in increased Xylometazoline, vasopressin, Nasal Morimoto et al., 1991; Lim et al., 2002. bioavailability gentamycin Absorption enhancer Pulmonary Insulin Morimoto et al., 2001; Surendrakumar et al., 2003. and dissolution rate modification Drobnik, 1991; Sakurai et al., 1997; Luo and Prestwich, 1999; Luo Taxol, superoxide dismutase, Drug carrier and facilitator of liposo- et al., 2000; Prisell et al., 1992; Yerushalmi et al., 1994; Yerushalmi Parenteral human recombinant insulin-like mal entrapment & Margalit, 1998; Peer & Margalit, 2000; growth factor, doxorubicin Eliaz & Szoka, 2001; Peer et al., 2003. Implant Dissolution rate modification Insulin Surini et al., 2003; Takayama et al., 1990. Dissolution rate modification Gene Plasmid DNA/monoclonal antibodies Yun et al., 2004; Kim et al., 2003. and protection Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Cosmetic uses of hyaluronic acid result, the concentration of hyaluronan increases and a HA has been extensively utilized in cosmetic products gel structure of micrometric thickness is formed which because of its viscoelastic properties and excellent bio- protects the cartilage surfaces from frictional damage compatibility. Application of HA containing cosmetic (Hlavacek, 1993). This mechanism to form a protective products to the skin is reported to moisturize and restore layer is much less effective in arthritis when the synovial elasticity, thereby achieving an antiwrinkle effect, albeit hyaluronan has both a lower concentration and a lower so far no rigorous scientific proof exists to substantiate molecular weight than normal. Another change in the this claim. HA-based cosmetic formulations or sun- arthritic joint is the protein composition of the synovial screens may also be capable of protecting the skin against fluid. Fraser et al. (1972) showed more than 40 years ago ultraviolet irradiation due to the free radical scavenging that addition of various serum proteins to hyaluronan properties of HA (Manuskiatti & Maibach, 1996). substantially increased the viscosity and this has received HA, either in a stabilized form or in combination with a renewed interest in view of recently discovered hyalad- other polymers, is used as a component of commercial herins (see above). TSG-6 and inter-α-trypsin inhibitor dermal fillers (e.g. Hylaform®, Restylane® and Dermalive®) and other acute phase reactants such as haptoglobin are in cosmetic surgery. It is reported that injection of such concentrated to arthritic synovial fluid (Hutadilok et al., products into the dermis, can reduce facial lines and 1988). It is not known to what extent these are affecting wrinkles in the long term with fewer side-effects and the rheology and lubricating properties. better tolerability compared with the use of collagen (Duranti et al., 1998; Bergeret-Galley et al., 2001; Leyden Scavenger functions et al., 2003). The main side-effect may be an allergic reac- Hyaluronan has also been assigned scavenger functions tion, possibly due to impurities present in HA (Schartz, in the joints. It has been known since the 1940s that 1997; Glogau, 2000). hyaluronan is degraded by various oxidizing systems and ionizing irradiation and we know today that the common denominator is a chain cleavage induced by free Biological function of hyaluronan radicals, essentially hydroxy radicals (Myint et al., 1987). Through this reaction hyaluronan acts as a very efficient Naturally, hyaluronan has essential roles in body func- scavenger of free radicals. Whether this has any biological tions according to organ type in which it is distributed importance in protecting the joint against free radicals is (Laurent et al., 1996). unknown. The rapid turnover of hyaluronan in the joints has led to the suggestion that it also acts as a scavenger Space fi ller for cellular debris (Laurent et al., 1995). Cellular material The specific functions of hyaluronan in joints are still could be caught in the hyaluronan network and removed essentially unknown. The simplest explanation for its at the same rate as the polysaccharide (Stankovska et al., presence would be that a f low of hyaluronan through the 2007; Rapta, et al., 2009). joint is needed to keep the joint cavity open and thereby allow extended movements of the joint. Hyaluronan is Regulation of cellular activities constantly secreted into the joint and removed by the As discussed above, more recently proposed functions synovium. The total amount of hyaluronan in the joint of hyaluronan are based on its specific interactions with cavity is determined by these two processes. The half-life hyaladherins. One interesting aspect is the fact that hyal- of the polysaccharide at steady-state is in the order of uronan inf luences angiogenesis but the effect is different 0.5–1 day in rabbit and sheep (Brown et al., 1991; Fraser depending on its concentration and molecular weight et al., 1993). The volume of the cavity is determined by the (Sattar et al., 1992). High molecular weight and high pressure conditions (hydrostatic and osmotic) in the cav- concentrations of the polymer inhibit the formation of ity and its surroundings. Hyaluronan could, by its osmotic capillaries, while oligosaccharides can induce angiogen- contributions and its formation of flow barriers in the esis. There are also reports of hyaluronan receptors on limiting layers, be a regulator of the pressure and f low rate vascular endothelial cells by which hyaluronan could act (McDonald & Leviek, 1995). It is interesting that in fetal on the cells (Edwards et al., 1995). The avascularity of the development the formation of joint cavities is parallel with joint cavity could be a result of hyaluronan inhibition of a local increase in hyaluronan (Edwards et al., 1994). angiogenesis. Another interaction of some interest in the joint Lubrication is the binding of hyaluronan to cell surface proteins. Hyaluronan has been regarded as an ideal lubricant in Lymphocytes and other cells may find their way to joints the joints due to its shear-dependent viscosity (Ogston & through this interaction. Injection of high doses of hyal- Stanier, 1953) but its role in lubrication has been refuted uronan intra-articularly could attract cells expressing by others (Radin et al., 1970). However, there are now these proteins. Cells can also change their expression of reasons to believe that the function of hyaluronan is to hyaluronan-binding proteins in states of disease, whereby form a film between the cartilage surfaces. The load on hyaluronan may influence immunological reactions and the joints may press out water and low-molecular solutes cellular traffic in the path of physiological processes from the hyaluronan layer into the cartilage matrix. As a in cells (Edwards et al., 1995). The observation often ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central reported that intra-articular injections of hyaluronan f. Termination phase: quick formation of alkoxy- alleviate pain in joint disease (Adams, 1993) may indicate type C-fragments and the fragments with a termi- a direct or indirect interaction with pain receptors. nal C=O group due to the glycosidic bond scission of hyaluronan. Alkoxy-type C fragments may continue the propagation phase of the free-radical Hyaluronan and synovial fl uid hyaluronan degradation reaction. Both fragments are represented by reduced molar masses (Kogan, In normal/healthy joint, the synovial f luid, which consists 2011; Rychly et al., 2006; Hrabarova et al., 2012; of an ultrafiltrate of blood plasma and glycoproteins con- Surovcikova et al., 2012; Valachova et al., 2013b; tains HA macromolecules of molar mass ranging between Banasova et al., 2012). 6–10 mega Daltons (Praest et al., 1997). SF serves also as a Several thiol compounds have attracted much atten- lubricating and shock absorbing boundary layer between tion from pharmacologists because of their reactivity moving parts of synovial joints. SF reduces friction and toward endobiotics such as hydroxyl radical-derived spe- wear and tear of the synovial joint playing thus a vital role cies. Thiols play an important role as biological reductants in the lubrication and protection of the joint tissues from (antioxidants) preserving the redox status of cells and damage during motion (Oates et al., 2002). protecting tissues against damage caused by the elevated As SF of healthy humans exhibits no activity of reactive oxygen/nitrogen species (ROS/RNS) levels, by hyaluronidase, it has been inferred that oxygen-derived which oxidative stress might be indicated. free radicals are involved in a self-perpetuating process Soltes and his coworkers examined the effect of sev- of HA catabolism within the joint (Grootveld et al., eral thiol compounds on inhibition of the degradation 1991; Stankovska et al., 2006; Rychly et al., 2006). This kinetics of a high-molecular-weight HA in vitro. High radical-mediated process is considered to account for ca. molecular weight hyaluronan samples were exposed twelve-hour half-life of native HA macromolecules in SF. to free-radical chain degradation reactions induced by Acceleration of degradation of high-molecular-weight ascorbate in the presence of Cu(II) ions, the so called HA occurring under inflammation and/or oxidative stress is accompanied by impairment and loss of its visco- elastic properties (Parsons et al., 2002; Soltes et al., 2005; Ac H OH Stankovska et al., 2005; Lath et al., 2005; Hrabarova et al., OH NH COOH C C C O HO O O HO 2007; Valachova & Soltes, 2010; Valachova et al., 2013a). O O HO HO HOOC OH NH Low-molecular weight HA was found to exert different OH Ac H O 2 OH biological activities compared to the native high-molecu- lar-weight biopolymer. HA chains of 25–50 disaccharide Ac H OH COOH OH NH C C C O units are inf lammatory, immune-stimulatory, and highly HO O O HO O O HO HO angiogenic. HA fragments of this size appear to func- O OH HOOC NH OH Ac tion as endogenous danger signals, reflecting tissues 2 under stress (Noble, 2002; West et al., 1985; Soltes et al., 2007; Stern et al., 2007; Soltes & Kogan, 2009). Figure 5 Ac OH NH COOH OH C O describes the fragmentation mechanism of HA under free C C C HO O O HO O O HO radical stress. HO HOOC OH NH OH Ac A HA a. Initiation phase: the intact hyaluronan macromol- ecule entering the reaction with the HO radical HO Ac H OH formed via the Fenton-like reaction: NH COOH OH C C C C HO O O HO + 2+ • – Cu + H O  Cu + HO + OH O O 2 2 HO HO O O HOOC OH NH H O has its origin due to the oxidative action of OH Ac 2 2 II I Cu Cu the Weissberger system (see Figure 6) OH b. Formation of an alkyl radical (C-centered hyal- • H Ac OH uronan macroradical) initiated by the HO radical NH COOH OH C O C C C HO O O HO attack. O O HO HO c. Propagation phase: formation of a peroxy-type HOOC OH NH OH Ac C-macroradical of hyaluronan in a process of oxygenation after entrapping a molecule of O . Ac H OH d. Formation of a hyaluronan-derived hydroper- OH NH COOH C C C C O HO O O HO oxide via the reaction with another hyaluronan O O H O HO 2 O O HOOC OH NH macromolecule. OH Ac e. Formation of highly unstable alkoxy-type C-macroradical of hyaluronan on undergoing Figure 5. Schematic degradation of HA under free radical stress a redox reaction with a transition metal ion in a (Hrabarova et al., 2012). reduced state. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Weissberger’s oxidative system. The concentrations of l-Glutathione (GSH; l-γ-glutamyl-l-cysteinyl-glycine; both reactants [ascorbate, Cu(II)] were comparable to a ubiquitous endogenous thiol, maintains the intracel- those that may occur during an early stage of the acute lular reduction-oxidation (redox) balance and regulates phase of joint inflammation (see Figure 6) (Banasova et signaling pathways during oxidative stress/conditions. al., 2011; Valachova et al., 2011; Soltes et al., 2006a; Soltes GSH is mainly cytosolic in the concentration range of et al., 2006b; Stankovska et al., 2004; Soltes et al., 2006c; ca. 1–10 mM; however, in the plasma as well as in SF, the Soltes et al., 2007; Valachova et al., 2008; 2009; 2010; 2011; range is only 1–3 μM (Haddad & Harb, 2005). This unique 2013; Hrabarova et al., 2009, 2011; Rapta et al., 2009; 2010; thiol plays a crucial role in antioxidant defense, nutrient Surovcikova-Machova et al., 2012; Banasova et al., 2011; metabolism, and in regulation of pathways essential for Drafi et al., 2010; Fisher & Naughton, 2005). the whole body homeostasis. Depletion of GSH results in Figure 7 illustrates the dynamic viscosity of hyaluro- an increased vulnerability of the cells to oxidative stress nan solution in the presence and absence of bucillamine, (Hultberg & Hultberg, 2006). d-penicillamine and l-cysteine as inhibitors for free radi- It was found that l-glutathione exhibited the most cal degradation of HA. The study showed that bucillamine significant protective and chain-breaking antioxidative to be both a preventive and chain-breaking antioxidant. effect against hyaluronan degradation. Thiol antioxida- On the other hand, d-penicillamine and l-cysteine dose tive activity, in general, can be inf luenced by many factors dependently act as scavenger of OH radicals within the such as various molecule geometry, type of functional first 60 min. Then, however, the inhibition activity is lost groups, radical attack accessibility, redox potential, thiol and degradation of hyaluronan takes place (Valachova et al., concentration and pK , pH, ionic strength of solution, as 2011; Valachova et al., 2009; 2010; Hrabarova et al., 2009). well as different ability to interact with transition metals (Hrabarova et al., 2012). Figure 8 shows the dynamic viscosity versus time profiles of HA solution stressed to degradation with Weissberger’s oxidative system. As evident, addition of different concentrations of GSH resulted in a marked pro- H H O O tection of the HA macromolecules against degradation. + Cu(II) + O O Cu (I) The greater the GSH concentration used, the longer was O O CH OH 2 CH OH the observed stationary interval in the sample viscosity CH OH 2 CH OH values. At the lowest GSH concentration used, i.e. 1.0 μM (Figure 8), the time-dependent course of the HA degrada- tion was more rapid than that of the reference experiment with the zero thiol concentration. Thus, one could classif y O O + H GSH traces as functioning as a pro-oxidant. + Cu(II) + H O O Cu (I) 2 2 O The effectiveness of antioxidant activity of 1,4-dithio- CH OH CH OH erythritol expressed as the radical scavenging capacity was CH OH 2 CH OH studied by a rotational viscometry method (Hrabarova et al., 2010). 1,4-dithioerythritol, widely accepted and used as an effective antioxidant in the field of enzyme and Figure 6. Scheme. Generation of H O by Weissberger’s system 2 2 protein oxidation, is a new potential antioxidant standard from ascorbate and Cu(II) ions under aerobic conditions (Vala- exhibiting very good solubility in a variety of solvents. chova et al., 2011) Figure 9 describes the effect of 1,4-dithioerythritol on 10 10 100 50 6 6 4 4 AB C 060 120 180 240 300 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Time [min] Figure 7. Eff ect of A) L-penicillamine, B) L-cysteine and C) bucillamine with diff erent concentrations (50, 100 μM) on HA degradation induced by the oxidative system containing 1.0 μM CuCl + 100 μM ascorbic acid (Valachova et al., 2011). ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Dynamic viscosity [mPa·s] Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central 11 11 10 10 3 4 5 1 9 9 8 8 OH 7 0 7 SH 6 6 HS 5 5 OH 4 4 0 60 120 180 240 300 0 60 120 180 240 300 Time [min] Time [min] Figure 8. Comparison of the eff ect of L-glutathione on HA deg- radation induced by the system containing 1.0 μM CuCl plus 100 μM L-ascorbic acid. Concentration of L-glutathione in μM: Figure 9. Eff ect of 1,4-dithioerythritol (1) on HA degradation 1–1.0; 2–10; 3, 4, 5–50, 100, and 200. Concentration of reference induced by Weissberger’s oxidative system (0) (Hrabarova et al., experiment: 0–nil thiol concentration (Hrabarova et al., 2009; 2010). Valachova et al., 2010a). AB 6 6 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Figure 10. Evaluation of antioxidative eff ects of N-acetyl-L-cysteine against high-molar-mass hyaluronan degradation in vitro induced by Weissberger´s oxidative system. Reference sample (black): 1 μM Cu(II) ions plus 100 μM ascorbic acid; nil thiol concentration. N-Acetyl-L- cysteine addition at the onset of the reaction (A) and after 1 h (B) (25, 50,100 μM). (Hrabarova et al., 2012). degradation of HA solution under free radical stress Investigation of the antioxidative effect of N-Acetyl- (Hrabarova et al., 2010). l-cysteine. Unlike l-glutathione, N-acetyl-l-cysteine was N-Acetyl-l-cysteine (NAC), another significant pre- found to have preferential tendency to reduce Cu(II) ions to cursor of the GSH biosynthesis, has broadly been used as Cu(I), forming N-acetyl-l-cysteinyl radical that may sub- •– effective antioxidant in a form of nutritional supplement sequently react with molecular O to give O (Soloveva et 2 2 (Soloveva et al., 2007; Thibodeau et al., 2001). At low con- al., 2007; Thibodeau et al., 2001). Contrary to l-cysteine, centrations, it is a powerful protector of α -antiproteinase NAC (25 and 50 μM), when added at the beginning of the against the enzyme inactivation by HOCl. NAC reacts reaction, exhibited a clear antioxidative effect within ca. 60 with HO radicals and slowly with H O ; however, no and 80 min, respectively (Figure 10A). Subsequently, NAC 2 2 reaction of this endobiotic with superoxide anion radical exerted a modest pro-oxidative effect, more profound was detected (Aruoma et al., 1989). at 25-μM than at 100-μM concentration (Figure  10A). Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Dynamic viscosity [mPa·s] Dynamic viscosity [mPa·s] Dynamic viscosity [mPa·s] Hyaluronan and synovial joint Tamer Mahmoud Tamer AB 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Figure 11. Evaluation of antioxidative eff ects of cysteamine against high-molar-mass hyaluronan degradation in vitro induced by Weissberger´s oxidative system. Reference sample (black): 1 mM CuII ions plus 100 μM ascorbic acid; nil thiol concentration. Cysteamine addition at the onset of the reaction (a) and after 1 h (b) (25, 50,100 μM). (Hrabarova et al., 2012). Adams ME. (1993). Viseosupplementation: A treatment for osteoarthritis. J Application of NAC 1 h after the onset of the reaction Rheumatol 20: Suppl. 39: 1–24. (Figure 10B) revealed its partial inhibitory effect against Altman RD. (2000). Intra-articular sodium hyaluronate in osteoarthritis of the formation of the peroxy-type radicals, independently knee. Semin Arthritis Rheum 30: 11–18. from the concentration applied (Hrabarova et al., 2012). Aruoma OI, Halliwell B, Hoey BM, Butler J. (1989). The antioxidant action of An endogenous amine, cysteamine (CAM) is a cystine- N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, su- depleting compound with antioxidative and anti-inflam- peroxide, and hypochlorous acid. Free Radic Biol Med 6: 593. matory properties; it is used for treatment of cystinosis – a Ashhurst DE, Bland YS, Levick JR. (1991). An immunohistochemical study of metabolic disorder caused by deficiency of the lysosomal the collagens of rabbit synovial interstitium. J Rheumatol 18: 1669–1672. cystine carrier. CAM is widely distributed in organisms Athanasou NA, Quinn J. (1991). Immunocytochemical analysis of human sy- novial lining cells: phenotypic relation to other marrow derived cells. Ann and considered to be a key regulator of essential metabolic Rheum Dis 50: 311–315. pathways (Kessler et al., 2008). Balazs EA, Denlinger JL. (1989). Clinical uses of hyaluronan. Ciba Found Symp Investigation of the antioxidative effect of cysteamine. 143: 265–280. Cysteamine (100 μM), when added before the onset of the Balazs EA, Laurent TC, Jeanloz RW. (1986). Nomencla ture of hyaluronic acid. reaction, exhibited an antioxidative effect very similar to Biochemical Journal 235: 903. that of GSH (Figure 8A and Figure 11A). Moreover, the Balazs EA. (2003). Analgesic eff ect of elastoviscous hyaluronan solutions and same may be concluded when applied 1 h after the onset the treatment of arthritic pain. Cells Tissues Organs 174: 49–62. of the reaction (Figure 11B) at the two concentrations (50 Balazs EA, Denlinger JL. (1993). Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol 20: 3–9. and 100 μM), suggesting that CAM may be an excellent Banasova M, Valachova K, Juranek I, Soltes L. (2012). Eff ect of thiol com- scavenger of peroxy radicals generated during the peroxi- pounds on oxidative degradation of high molar hyaluronan in vitro. Inter- dative degradation of HA (Hrabarova et al., 2012). discip Toxicol 5(Suppl. 1): 25–26. Banasova M, Valachova K, Juranek I, Soltes L. (2013b). Aloevera and methyl- sulfonylmethane as dietary supplements: Their potential benefi ts for ar- Acknowledgements thritic patients with diabetic complications. Journal of Information Intelli- gence and Knowledge 5: 51–68. Banasova M, Valachova K, Rychly J, Priesolova E, Nagy M, Juranek I, Soltes L. The author would like to thank the Institute of (2011). Scavenging and chain breaking activity of bucillamine on free-rad- Experimental Pharmacology & Toxicology for having ical mediated degradation of high molar mass hyaluronan. ChemZi 7: 205– invited him and oriented him in the field of medical research. He would also like to thank Slovak Academic Baňasová M, Valachová K, Hrabárová E, Priesolová E, Nagy M, Juránek I, Information Agency (SAIA) for funding him during his Šoltés L. (2011). Early stage of the acute phase of joint infl ammation. In vitro testing of bucillamine and its oxidized metabolite SA981 in the function of work in the Institute. antioxidants. 16th Interdisciplinary Czech-Slovak Toxicological Conference in Prague. Interdiscip Toxicol 4(2): 22. Barrett J P, Siviero P. (2002). Retrospective study of outcomes in Hyalgan(R)- treated patients with osteoarthritis of the knee. Clin Drug Invest 22: 87–97. REFERENCES Bergeret-Galley C, Latouche X, Illouz Y G.(2001). The value of a new fi ller ma- Abeydeera LR. (2002). In vitro production of embryos in swine. Theriogenol- terial in corrective and cosmetic surgery: DermaLive and DermaDeep. Aes- ogy 57: 257–273. thetic Plast Surg 25: 249–255. ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Dynamic viscosity [mPa·s] Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Bernatchez SF, Tabatabay C, Gurny R. (1993). Sodium hyaluronate 0.25-per- Edwards JCW (1995). Consensus statement. Second international meeting cent used as a vehicle increases the bioavailability of topically adminis- on synovium. Cell biology, physiology and pathology. Ann Rheum Dis 54: tered gentamicin. Graefes Arch Clin Exp Ophthalmol 231: 157–161. 389–91. Betts WH, Cleland LG. (1982): Eff ect of metal chelators and antiinfl ammatory Eliaz RE, Szoka FC. (2001). Liposome-encapsulated doxorubicin targeted to drugs on the degradation of hyaluronic acid. Arthritis Rheum 25: 1469–1476. CD44: a strategy to kill CD44-overexpressing tumor cells. Cancer Res 61: 2592–2601. Blake DR, Hall ND, Treby DA. (1981). Protection against superoxide and hy- drogen peroxide in synovial fl uid from rheumatoid patients. Clin Sci 61: Figueiredo F, Jones GM, Thouas GA, Trounson AO. (2002). The eff ect of extra- 483–486. cellular matrix molecules on mouse preimplantation embryo development in vitro. Reprod Fertil Dev 14: 443–451. Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. (2007). A model of synovial fl uid lubricant composition in normal and injured. Euro- Fisher AE, Naughton ODP. (2005). Therapeutic chelators for the twenty fi rst pean cells and materials 13: 26–39. century: new treatments for iron and copper mediated infl ammatory and neurological disorders. Curr Drug Delivery 2: 261–268. Bothner H, Wik O. (1987). Rheology of hyaluronate. Acta Otolaryngol Suppl 442: 25–30. Fraser JRE, Foo WK, Maritz JS. (1972). Viscous interactions of hyaluronic acid with some proteins and neutral saccharides. Ann Rheum Dis 31: 513–20. Brandt K. (1970). Modifi cation of chemotaxis by synovial fl uid hyaluronate. Arthritis Rheum 13: 308–309. Fraser JRE, Kimpton WG, Pierscionek BK, Cahill RNP. (1993). The kinetics of hyaluronan in normal and acutely infl amed synovial joints – observations Brown MB, Jones SA. (2005). Hyaluronic acid: a unique topical vehicle for with experimental arthritis in sheep. Semin Arthritis Rheum 22: 9–17. the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol 19: 308–318. Furnus CC, de Matos DG, Mar tinez AG. (1998). Eff ec t of hyaluronic acid on devel- opment of in vitro produced bovine embryos. Theriogenology 49: 1489–99. Brown TJ, Laurent UBG, Fraser JRE. (1991). Turnover of hyaluronan in synovial joints: elimination of labelled hyaluronan from the knee joints of the rab- Gandolfi SA, Massari A, Orsoni JG. (1992). Low-molecular-weight sodium hy- bit. Exp Physiol 76: 125–34. aluronate in the treatment of bacterial corneal ulcers. Graefes Arch Clin Exp Ophthalmol 230: 20–23. Bucolo C, Mangiafi co P. (1999). Pharmacological profi le of a new topical pilo- carpine formulation. J Ocul Pharmacol Ther 15: 567–573. Gardner DK, Lane M, Stevens J, Schoolcraft WB. (2003). Changing the start temperature and cooling rate in a slow-freezing protocol increases human Bucolo C, Spadaro A, Mangiafi co S. (1998). Pharmacological evaluation of a new timolol/pilocarpine formulation. Ophthalmic Res 30: 101–106. blastocyst viability. Fertil Steril 79: 407–410. Gardner DK, Rodriegez-Martinez H, Lane M. (1999). Fetal development after Camber O, Edman P, Gurny R. (1987). Infl uence of sodium hyaluronate on the meiotic eff ect of pilocarpine in rabbits. Curr Eye Res 6: 779–784. transfer is increased by replacing protein with the glycosaminoglycan hyal- uronan for mouse embryo culture and transfer. Hum Reprod 14: 2575–2580. Camber O, Edman P. (1989). Sodium hyaluronate as an ophthalmic vehicle – some factors governing its eff ect on the ocular absorption of pilocarpine. Ghosh P, Guidolin D. (2002). Potential mechanism of action of intraarticular hyaluronan therapy in osteoarthritis: are the eff ects molecular weight de- Curr Eye Res 8: 563–567. pendent? Semin Arthritis Rheum 32: 10–37. Cantor JO, Cerreta JM, Armand G, Turino GM. (1998). Aerosolized hyaluronic Ghosh S, Jassal M. (2002). Use of polysaccharide fi bres for modem wound acid decreases alveolar injury induced by human neutrophil elastase. Proc Soc Exp Biol Med 217: 471–475. dressings. Indian J Fibre Textile Res 27: 434–450. Chabrecek P, Soltes L, Kallay Z, Fugedi A. (1990). Isolation and characteriza- Gibbs DA, Merrill EW, Smith KA, Balazs EA. (1968). Rheology of hyaluronic tion of high molecular weight (3H) hyaluronic acid. J Label Compd Radio- acid. Biopolymers 6: 777–91. pharm 28: 1121–1125. Glogau RG. (2000). The risk of progression to invasive disease. J Am Acad Der- Chabrecek P, Soltes L, Kallay Z, Novak I. (1990). Gel permeation chromato- matol 42: S23–S24. graphic characterization of sodium hyaluronate and its reactions prepared Grootveld M, Henderson EB, Farrell A, Blake DR, Parkes HG, Haycock P. (1991). by ultrasonic degradation. Chromatographia 30: 201–204. Oxidative damage to hyaluronate and glucose in synovial fl uid during ex- Chen FH, Rousche KT, Tuan RS. (2006). Technology Insight: adult stem cells ercise of the infl amed rheumatoid joint. Detection of abnormal low-mo- in cartilage regeneration and tissue engineering. Nat Clin Pract Rheumatol lecular-mass metabolites by proton-N.M.R. spectroscopy. Biochem J 273: 2(7): 373–82. 459–467. Coleman P, Kavanagh E, Mason RM, Levick JR, Ashhurst DE. (1998). The pro- Guidolin DD, Ronchetti IP, Lini E. (2001). Morphological analysis of articular teoglycans and glycosaminoglycan chains of rabbit synovium. Histochem cartilage biopsies from a randomized. clinical study comparing the eff ects J 30: 519–524. of 500–730 kDa sodium hyaluronate Hyalgan(R) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage 9: Comper WD, Laurent TC. (1978). Physiological function of connective tissue 371–381. polysaccharidcs. Physiol Rev 58: 255–315. Gurny R, Ibrahim H, Aebi A. (1987). Design and evaluation of controlled re- Cowman MK, Matsuoka S. (2005). Experimental ap proaches to hyaluronan lease systems for the eye. J Control Release 6: 367–373. structure. Carbohydrate Re search 340: 791–809. Haddad JJ, Harb HL. (2005). L-gamma-Glutamyl-L-cysteinyl-glycine (glutathi- Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K. (1985). Concentration and one; GSH) and GSH-related enzymes in the regulation of pro- and anti-in- molecular weight of sodium hyaluronate in synovial fl uid from patients with fl ammatory cytokines: a signaling transcriptional scenario for redox(y) im- rheumatoid arthritis and other arthropathies. Ann Rheum Dis 44: 817–822. munologic sensor(s). Mol Immunol 42: 987–1014. Dobbie JW, Hind C, Meijers P, Bodart C, Tasiaux N, Perret J, Anderson JD. Hamburger MI, Lakhanpal S, Mooar PA, Oster D. (2003). Intra-articular hyal- (1995). Lamellar body secretion: ultrastructural analysis of an unexplored uronans: a review of product-specifi c safety profi les. Semin Arthritis Rheum function of synoviocytes. Br J Rheumatol 34: 13–23. 32: 296–309. Dougados M. (2000). Sodium hyaluronate therapy in osteoarthritis: argu- Haubeck HD, Kock R, Fischer DC, van de Leur E, Hoff meister K, Greiling H. ments for a potential benefi cial structural eff ect. Semin Arthritis Rheum 30: (1995). Transforming growth factor ß1, a major stimulator of hyaluronan 19–25. synthesis in human synovial lining cells. Arthritis Rheum 38: 669–677. Dráfi F, Valachová K, Hrabárová E, Juránek I, Bauerová K, Šoltés L. (2010). Herrero-Vanrell R, Fernandez-Carballido A, Frutos G, Cadorniga R. (2000). En- Study of methotrexate and β-alanyl-L-histidine in comparison with L-glu- tathione on high-molar-mass hyaluronan degradation induced by ascor- hancement of the mydriatic response to tropicamide by bioadhesive poly- mers. J Ocul Pharmacol Ther 16: 419–428. bate plus Cu (II) ions via rotational viscometry. 60th Pharmacological Days in Hradec Králové. Acta Medica 53(3): 170. Hills BA, Crawford RW. (2003) Normal and prosthetic synovial joints are lu- bricated by surface-active phospholipid: a hypothesis. J Arthroplasty 18: Drobnik J. (1991). Hyaluronan in drug delivery. Adv Drug Dev Rev 7: 295–308. 499–505. Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. (1998). Injectable hyal- Hlavacek M. (1993). The role of synovial fl uid fi ltration by cartilage in lubrica- uronic acid gel for soft tissue augmentation – a clinical and histological study. Dermatol Surg 24: 1317–1325. tion of synovial joints. J Biomech 26(10): 1145–50. Edwards JCW, Wilkinson LS, Jones HM. (1994). The formation of human syno- Hochberg MC. (2000). Role of intra-articular hyaluronic acid preparations in vial cavities: a possible role for hyaluronan and CD44 in altered interzone medical management of osteoarthritis of the knee. Semin Arthritis Rheum cohesion. J Anat 185: 355–67. 30: 2–10. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Hrabarova E, Valachova K, Rapta P, Soltes L. (2010). An alternative standard Knight AD, Levick JR. (1984). Morphometry of the ultrastructure of the blood- for trolox-equivalent antioxidant-capacity estimation based on thiol an- joint barrier in the rabbit knee. Q J Exp Physiol 69: 271–288. tioxidants. Comparative 2,2’-azinobis[3-ethylbenzothiazoline-6-sulfonic Kogan G. (2010). Hyaluronan – A High Molar mass messenger reporting on the acid] decolorization and rotational viscometry study regarding hyaluronan status of synovial joints: part 1. Physiological status In: New Steps in Chemical degradation. Chemistry & Biodiversity 7(9): 2191–2200. and Biochemical Physics. ISBN: 97 8-1-61668-923 -0. pp. 121–133. Hrabarova E, Valachova K, Rychly J, Rapta P, Sasinkova V, Malikova M, Soltes L. Kogan G, Soltes L, Stern R, Mendichi R. (2007a). Hyaluronic acid: A biopoly- (2009). High-molar-mass hyaluronan degradation by Weissberger’s system: mer with versatile physico-chemical and biological properties. Chapter 31 – Pro- and anti-oxidative eff ects of some thiol compounds. Polymer Degrada- in: Handbook of Polymer Research: Monomers, Oligomers, Polymers and tion and Stability 94: 1867–1875. Composites. Pethrick R. A, Ballada A, Zaikov G. E. (eds.), Nova Science Pub- Hrabarova E, Valachova K, Juranek I, Soltes L. (2012). Free-radical degrada- lishers, New York, pp. 393–439. tion of high-molar-mass hyaluronan induced by ascorbate plus cupric ions: Kogan G, Soltes L, Stern R, Gemeiner P. (2007). Hyaluronic acid: A natural bio- evaluation of antioxidative eff ect of cysteine-derived compounds. Chemis- polymer with a broad range of biomedical and industrial applications. Bio- try & Biodiversity 9: 309–317. technol Lett 29: 17–25. Hrabarova E, Gemeiner P, Soltes L. (2007). Peroxynitrite: In vivo and in vitro Kreil G. (1995). Hyaluronidases-A group of neglected enzymes. Protein Sci- synthesis and oxidant degradative action on biological systems regarding ences 4: 1666–1669. biomolecular injury and infl ammatory processes. Chem Pap 61: 417–437. Lane M, Maybach JM, Hooper K. (2003). Cryo-survival and development of Hrabárová E, Valachová K, Juránek I, Šoltés L. (2011). Free-radical degradation bovine blastocysts are enhanced by culture with recombinant albumin of high-molar-mass hyaluronan induced by ascorbate plus cupric ions. Anti- and hyaluronan. Mol Reprod Dev 64: 70–78. oxidative properties of the Piešťany-spa curative waters from healing peloid and maturation pool. In: “Kinetics, Catalysis and Mechanism of Chemical Re- Langer K, Mutschler E, Lambrecht G. (1997). Methylmethacrylate sulfopropyl- actions” G. E. Zaikov (eds), Nova Science Publishers, New York, pp. 29–36. methacrylate copolymer nanoparticles for drug delivery – Part III. Evalua- tion as drug delivery system for ophthalmic applications. Int J Pharm 158: Hrabárová E, Valachová K, Rychlý J, Rapta P, Sasinková V, Gemeiner P, Šoltés 219–231. L. (2009). High-molar-mass hyaluronan degradation by the Weissberger´s system: pro- and antioxidative eff ects of some thiol compounds. Polym De- Lath D, Csomorova K, Kollarikova G, Stankovska M, Soltes L. (2005). Molar grad Stab 94: 1867–1875. mass-intrinsic viscosity relationship of high-molar-mass yaluronans: In- volvement of shear rate. Chem Pap 59: 291–293. Hultberg M, Hultberg B. (2006). The eff ect of diff erent antioxidants on glu- tathione turnover in human cell lines and their interaction with hydrogen Laurent TC, Laurent UBG, Fraser JRE. (1996). The structure and function of hy- peroxide. Chem Biol Interact 163(3): 192–198. aluronan: An over view. Immunology and Cell Biology 74: A1–A7. Hutadilok N. Ghosh P, Brooks PM. (1988). Binding of haptoglobin. inter-α- Laurent TC. (1989). The biology of hyaluronan. In: Ciba Foundation Sympo- trypsin inhibitor, and l proteinase inhibitor to synovial fl uid hyaluronate sium. John Wiley and Sons, New York. 143: 1–298. and the infl uence of these proteins on its degradation byoxygen derived Laurent TC, Fraser JRE. (1992). Hyaluronan. FASEB J 6: 2397–2404. free radicals. Ann Rheum Dis 47: 377–85. Laurent TC. Laurent UBG, Fraser JRE. (1995). Functions of hyaluronan. Ann Inoue M, Katakami C. (1993). The eff ect of hyaluronic-acid on corneal epithe- Rheum Dis 54: 429–32. lial-cell proliferation. Invest Ophthalmol Vis Sci 34: 2313–2315. Laurent TC, Ryan M, Pictruszkiewicz A. (1960). Fractionation of hyaluronic Itano N, Kimata K. (2002). Mammalian hyaluronan synthases. IUBMB Life 54: acid. The polydispersity of hyaluronic acid from the vitreous body. Biochim 195–199. Biophys Acta 42: 476–85. Jaakma U, Zhang B R, Larsson B. (1997). Eff ects of sperm treatments on the in Levick JR. (1994). An analysis of the interaction between interstitial plasma vitro development of bovine oocytes in semidefi ned and defi ned media. protein, interstitial fl ow, and fenestral fi ltration and its application to Theriogenology 48: 711–720. synovium. Microvasc Res 47: 90–125. Jang G, Lee BC, Kang SK, Hwang WS. (2003). Eff ect of glycosaminoglycans on the preimplantation development of embryos derived from in vitro fertil- Leyden J, Narins RS, Brandt F. (2003). A randomized, double-blind, multi- ization and somatic cell nuclear transfer. Reprod Fertil Dev 15: 179–185. center comparison of the effi cacy and tolerability of Restylane versus Zy- plast for the correction of nasolabial folds. Dermatol Surg 29: 588–595. Jarvinen K, Jarvinen T, Urtti A. (1995). Ocular absorption following topical de- livery. Adv Drug Dev Rev 16: 3–19. Lim ST, Forbes B, Berry DJ, Martin GP, Brown MB. (2002). In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal Jay GD, Britt DE, Cha DJ. (2000). Lubricin is a product of megakaryocyte stim- delivery of gentamicin in rabbits. Int J Pharm 231: 73–82. ulating factor gene expression by human synovial fi broblasts. J Rheumatol 27: 594–600. Luo Y, Prestwich GD. (1999). Synthesis and selective cytotoxicity of a hyal- uronic acid-antitumor bioconjugate. Bioconjug Chem 10: 755–763. Joly T, Nibart M, Thibier M. (1992). Hyaluronic-acid as a substitute for proteins in the deep-freezing of embryos from mice and sheep – an in vitro investi- Luo Y, Ziebell MR, Prestwich GD. (2000). A hyaluronic acid-taxol antitumor gation. Theriogenology 37: 473–480. bioconjugate targeted to cancer cells. Biomacromolecules 1: 208–218. Juranek I, Soltes L. (2012). Reactive oxygen species in joint physiology: Possible Maheu E, Ayral X, Dougados M. (2002). A hyaluronan preparation (500– mechanism of maintaining hypoxia to protect chondrocytes from oxygen ex- 730 kDa) in the treatment of osteoarthritis: a review of clinical trials with cess via synovial fl uid hyaluronan peroxidation. In: “Kinetics, Catalysis and Hyalgan(R). Int J Clin Pract 56: 804–813. Mechanism of Chemical Reactions: From Pure to Applied Science. Volume Manuskiatti W, Maibach HI. (1996). Hyaluronic acid and skin: wound healing 2 – Tomorrow and Perspectives” R.M. Islamova, S.V. Kolesov, G.E. Zaikov and aging. Int J Dermatol 35: 539–544. (eds), Nova Science Publishers, New York pp. 1–10 Mazzucco D, Scott R, Spector M. (2004). Composition of joint fl uid in patients Kano K, Miyano T, Kato S. (1998). Eff ects of glycosaminoglycans on the devel- undergoing total knee replacement and revision arthroplasty: correlation opment of in vitro matured and fertilized porcine oocytes to the blastocyst with fl ow properties. Biomaterials 25: 4433–4445. stage in vitro. Biol Reprod 58: 1226–1232. McCord JM. (1974). Free radicals and infl ammation: protection of synovial Kelly MA, Goldberg VM, Healy WL. (2003). Osteoarthritis and beyond: a con- fl uid by superoxide dismutase. Science 185: 529–531. sensus on the past, present, and future of hyaluronans in orthopedics. Or- thopedics 26: 1064–1079. McDonald JN, Levick JR. (1988). Morphology of surface synoviocytes in situ at normal and raised joint pressure, studied by scanning electron micros- Kemmann E. (1998). Creutzfeldt-Jakob disease (CJD) and assisted reproduc- copy. Ann Rheum Dis 47: 232–240. tive technology (ART) – quantifi cation of risks as part of informed consent. Hum Reprod 13: 1777. McDonald JN, Leviek JR. (1995). Eff ect of intra-articular hyaluronan on pres- sure-fl ow relation across synovium in anaesthetized rabbits. J Physiol Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, de Souza 485(Pt.1): 179 –93. Wyse AT, Wannmacher CMD. (2008). Antioxidant eff ect of cysteamine in brain cortex of young rats. Neurochem Res 33: 737–44. Mendichi R, Soltes L. (2002). Hyaluronan molecular weight and polydisper- Kim A, Checkla DM, Dehazya P, Chen WL. (2003). Characterization of DNA- sity in some commercial intra-articular injectable preparations and in sy- novial fl uid In amm fl Res 51: 115–116. hyaluronan matrix for sustained gene transfer. J Control Release 90: 81–95. Kirwan J. (2001). Is there a place for intra-articular hyaluronate in osteoarthri- Meyer K, Palmer JW. (1934). The polysaccharide of the vitreous humor. Jour- tis of the knee? Knee 8: 93–101. nal of Biology and Chemistry 107: 629–634. ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Miltner O, Schneider U, Siebert CH. (2002). Effi cacy of intraarticular hyal- Prisell PT, Camber O, Hiselius J, Norstedt G. (1992). Evaluation of hyaluronan uronic acid in patients with osteoarthritis–a prospective clinical trial. Os- as a vehicle for peptide growth factors. Int J Pharm 85: 51–56. teoarthritis Cartilage 10: 680–686. Radin EL, Swann DA, Weisser PA. (1970). Separation of a hyaluronate-frec lu- Miyano T, Hirooka RE, Kano K. (1994). Eff ects of hyaluronic-acid on the de- bricating fraction from synovial fl uid. Nature 228: 377–8. velopment of 1-cell and 2-cell porcine embryos to the blastocyst stage in- Rapta P, Valachova K, Gemeiner P, Soltes L. (2009). High-molar-mass hyaluro- vitro. Theriogenology 41: 1299–1305. nan behavior during testing its radical scavenging capacity in organic and aqueous media: Eff ects of the presence of Manganese (II) ions. Chem Bio- Miyazaki M, Sato S, Yamaguchi T. (1983). Analgesic and antiin ammat fl ory ac- tion of hyaluronic sodium, Japan Pharmacological Conference. Tokyo, April divers 6: 162–169. 4, 1983. Rapta P, Valachová K, Gemeiner P, Šoltés L. (2009). High-molar-mass hyaluro- Miyazaki T, Miyauchi S, Nakamura T. (1996). The eff ect of sodium hyaluronate nan behavior during testing its antioxidant properties in organic and aque- on the growth of rabbit cornea epithelial cells in vitro. J Ocul Pharmacol ous media: eff ects of the presence of Mn(II) ions. Chem Biodivers 6: 162–169. Ther 12: 409–415. Rapta P, Valachová K, Zalibera M, Šnirc V, Šoltés L. (2010). Hyaluronan degrada- Momberger TS, Levick JR, Mason RM. (2005). Hyaluronan secretion by syn- tion by reactive ox ygen species: scavenging eggect of the hexapyridoindole sto- badine and two of its derivatives. In Monomers, Oligomers, Polymers, Com- oviocytes is mechanosensitive. Matrix Biol 24: 510–519. posites, and Nanocomposites, Ed: R. A. Pethrick P. Petkov, A. Zlatarov G. E. Moreira CA, Armstrong DK, Jelliff e RW. (1991). Sodium hyaluronate as a car- Zaikov, S. K. Rakovsky, Nova Science Publishers, N.Y, Chapter 7, pp. 113–126. rier for intravitreal gentamicin – an experimental study. Acta Ophthalmol (Copenh) 69: 45–49. Rees MD, Kennett EC, Whitelock JM, Davies MJ. (2008). Oxidative damage to extracellular matrix and its role in human pathologies. Free Radical Biol. Moreira CA, Moreira AT, Armstrong DK. (1991). In vitro and in vivo studies with Med 44: 1973–2001. sodium hyaluronate as a carrier for intraocular gentamicin. Acta Ophthal- Revell PA. (1989). Synovial lining cells. Rheumatol Int 9: 49–51. mol (Copenh) 69: 50–56. Morimoto K, Metsugi K, Katsumata H. (2001). Eff ects of lowviscosity sodium Risberg B. (1997). Adhesions: preventive strategies. Eur J Surg 163: 32–39. hyaluronate preparation on the pulmonary absorption of rh-insulin in rats. Rittig M, Tittor F, Lutjen-Drecoll E, Mollenhauer J, Rauterberg J. (1992). Immu- Drug Dev Ind Pharm 27: 365–371. nohistochemical study of extracellular material in the aged human syno- vial membrane. Mech Ageing Dev 64: 219–234. Morimoto K, Yamaguchi H, Iwakura Y. (1991). Eff ects of viscous hyaluronate- sodium solutions on the nasal absorption of vasopressin and an analog. Rychly J, Soltes L, Stankovska M, Janigova I, Csomorova K, Sasinkova V, Kogan Pharmacol Res 8: 471–474. G, Gemeiner P. (2006). Unexplored capabilities of chemiluminescence and thermoanalytical methods in characterization of intact and degraded hyal- Morris ER, Rees DA, Welsh EJ. (1980). Conformation and dynamic interactions uronans. Polym Degrad Stab 91(12): 3174–3184. in hyaluronate solutions. J Mol Biol 138: 383–400. Saettone MF, Giannaccini B, Chetoni P, et al. (1991). Evaluation of highmolec- Myint P. (1987). The reactivity of various free radicals with hyaluronic acid ular-weight and low-molecular-weight fractions of sodium hyaluronate steady-state and pulse radiolysis studies. Biochim Biophys-Aeta 925: 194 –202. and an ionic complex as adjuvants for topical ophthalmic vehicles contain- Necas J, Bartosikova L, Brauner P, Kolar J. (2008). Hyaluronic acid (hyaluro- ing pilocarpine. Int J Pharm 72: 131–139. nan): a review. Veterinarni Medicina 53(8): 397–411. Saettone MF, Monti D, Torracca MT, Chetoni P. (1994). Mucoadhesive oph- Niwa Y, Sakane T, Shingu M, Yokoyama MM. (1983). Eff ect of stimulated neu- thalmic vehicles – evaluation polymeric low-viscosity formulations. J Ocul trophils from the synovial fl uid of patients with rheumatoid arthritis on Pharmacol 10: 83–92. lymphocytes: a possible role of increased oxygen radicals generated by Sakurai K, Miyazaki K, Kodera Y. (1997). Anti-infl ammatory activity of superox- the neutrophils. J Clin Immunol 3: 228–240. ide dismutase conjugated with sodium hyaluronate. Glycoconj J 14: 723–728. Noble PW. (2002). Hyaluronan and its catabolic products in tissue injury and Sasaki H, Yamamura K, Nishida K. (1996). Delivery of drugs to the eye by topi- repair. Matrix Biol 21: 25–29. cal application. Prog Retinal Eye Res 15: 583–620. Oates KMN, Krause WE, Colby RH. (2002). Using rheology to probe the mech- Sattar A, Kumar S, West DC. (1992). Does hyaluronan have a role in endothe- anism of joint lubrication: polyelectrolyte/protein interactions in synovial lial cell proliferation ofthe synovium. Semin. Arthritis Rheum 22: 37–43. fl uid. Mat Res Soc Syrnp Proc 711: 53–58. Schartz RA. (1997). The actinic keratoses. A perspective and update. Dermatol Ogston AG, Stanier JE. (1953). The physiological function of hyaluronic acid in Surg 23: 1009–1019. synovial fl uid viscous, elastic and lubricant properties. J Physiol 199: 244– Schiller J, Volpi N, Hrabarova E, Soltes L. (2011). Hyaluronic acid: a natural bio- polymer In: “Handbook of Biopolymers and Their Applications” S. Kalia and Ortonne JP. (1996). A controlled study of the activity of hyaluronic acid in the L. Averous (eds), Wiley & Scrivener Publishing, USA pp. 3–34. treatment of venous leg ulcers. J Dermatol Treatment 7: 75–81. Schmid T, Lindley K, Su J, Soloveychik V, Block J, Kuettner K, Schumacher B. Orvisky E, Soltes L, Chabrecek P, Novak I, Kery V, Stancikova M, Vins I. (1992). (2001a). Superfi cial zone protein (SZP) is an abundant glycoprotein in hu- The determination of hyaluronan molecular weight distribution by means man synovial fl uid and serum. Trans Orthop Res Soc 26: 82. of high perfeormance size exclusion chromatography. J Liq Chromatogr 15: 3203–3218. Schmid T, Soloveychik V, Kuettner K, Schumacher B. (2001b). Superfi cial zone protein (SZP) from human cartilage has lubrication activity. Trans Orthop Parsons BJ, Al-Assaf S, Navaratnam S, Phillips GO. (2002). Comparison of the Res Soc 26: 178. reactivity of diff erent oxidative species (ROS) towards hyaluronan, in: Kennedy JF, Phillips GO, Williams PA, Hascall VC (Eds.), Hyaluronan: Chemical, Bio- Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. (1994). A chemical and Biological Aspects, Woodhead, Publishing Ltd, Cambridge, novel proteoglycan synthesized and secreted by chondrocytes of the su- MA, pp. 141–150. perfi cial zone of articular cartilage. Arch Biochem Biophys 311: 144–152. Peer D, Florentin A, Margalit R. (2003). Hyaluronan is a key component in Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. (1999). cryoprotection and formulation of targeted unilamellar liposomes. Bio- Immunodetection and partial c DNA sequence of the proteoglycan, super- chim Biophys Acta-Biomembranes 1612: 76–82. fi cial zone protein, synthesized by cells lining synovial joints. J Orthop Res 17: 110–120. Peer D, Margalit R. (2000). Physicochemical evaluation of a stability-driven approach to drug entrapment in regular and in surface-modifi ed lipo- Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL. (2005). Proteo- somes. Arch Biochem Biophys 383: 185–190. glycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J Orthop Res 23: 562–568. Poli A, Mason RM, Levick JR. (2004). Eff ects of Arg- Gly-Asp sequence peptide and hyperosmolarity on the permeability of interstitial matrix and fenes- Schwarz IM, Hills BA. (1996). Synovial surfactant: lamellar bodies in type B trated endothelium in joints. Microcirculation 11: 463–476. synoviocytes and proteolipid in synovial fl uid and the articular lining. Br J Rheumatol 35: 821–827. Praest BM, Greiling H, Kock R. (1997). Eff ects of oxygen-derived free radicals on the molecular weight and the polydispersity of hyaluronan solutions. Schwarz IM, Hills BA. (1998). Surface-active phospholipids as the lubricating Carbohydr Res 303 :153–157 . component of lubricin. Br J Rheumatol 37: 21–26. Price FM, Levick JR, Mason RM. (1996). Glycosaminoglycan concentration in Scott DL, Shipley M, Dawson A, Edwards S, Symmons DP, Woolf AD. (1998). synovium and other tissues of rabbit knee in relation to synovial hydraulic The clinical management of rheumatoid arthritis and osteoarthritis: strate- resistance. J Physiol (Lond) 495: 803–820. gies for improving clinical eff ectiveness. Br J Rheumatol 37: 546–554. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Scott JE, Cummings C, Brass A, Chen Y. (1991). Secondary and tertiary struc- Surini S, Akiyama H, Morishita M. (2003). Polyion complex of chitosan and so- tures of hyaluronan in aqueous solution, investigated by rotary shadowing- dium hyaluronate as an implant device for insulin delivery. STP Pharm Sci electron microscopy and computer simulation. Biochem J 274: 600–705. 13: 265–268. Servaty R, Schiller J, Binder H, Arnold K. (2000). Hydration of polymeric com- Surovcikova L, Valachova K , Banasova M, Snirc V, Priesolova E, Nagy M, Juranek ponents of the cartilage – An infrared spectroscopic study on hyaluronic I, Soltes L. (2012). Free-radical degradation of high-molar-mass hyaluronan acid and chondroitin sulfate. Int J Biol Macromol 28: 123–129. induced by ascorbate plus cupric ions: Testing of stobadine and its two derivatives in function as antioxidants. General Physiol Biophys 31: 57–64. Simkovic I, Hricovini M, Soltes L, Mendichi R, Cosentino C. (2000). Preparation of water soluble/insoluble derivatives of Hyaluronic acid by cross linking Swann DA, Silver FH, Slayter HS, Staff ord W, Shore E. (1985). The molecular with epichlorohydrin in aqueous NaOH/NH OH solution. Carbohydr Polym structure and lubricating activity of lubricin isolated from bovine and hu- 41: 9–14. man synovial fl uids. Biochem J 225: 195–201. Simon A, Safran A, Revel A. (2003). Hyaluronic acid can successfully replace Takayama K, Hirata M, Machida Y. (1990). Eff ect of interpolymer complex-for- albumin as the sole macromolecule in a human embryo transfer medium. mation on bioadhesive property and drug release phenomenon of com- Fertil Steril 79: 1434–1438. pressed tablet consisting of chitosan and sodium hyaluronate. Chem Phar- maceut Bull 38: 1993–1997. Soldati D, Rahm F, Pasche P. (1999). Mucosal wound healing after nasal sur- gery. A controlled clinical trial on the effi cacy of hyaluronic acid containing Tani E, Katakami C, Negi A (2002). Eff ects of various eye drops on corneal cream. Drugs Exp Clin Res 25: 253–261. wound healing after superfi cial keratectomy in rabbits. Jpn J Ophthalmol 46: 488–495. Soloveva ME, Solovev VV, Faskhutdinova AA, Kudryavtsev AA, Akatov VS. (2007). Prooxidant and cytotoxic action of N-acetylcysteine and glutathi- Tascioglu F, Oner C. (2003). Effi cacy of intra-articular sodium hyaluronate in one in combinations with vitamin B12b. Cell Tissue Biol 1: 40–49. the treatment of knee osteoarthritis. Clin Rheumatol 22: 112–117. Soltes L, Kogan G. (2009). Impact of transition metals in the free-radical degra- Thibodeau PA, Kocsis-Bedard S, Courteau J, Niyonsenga T, Paquette B. (2001). dation of hyaluronan biopolymer In: “Kinetics & Thermodynamics for Chem- Thiols can either enhance or suppress DNA damage induction by catecho- istry & Biochemistry: Vol. 2” E. M. Pearce, G. E. Zaikov, G. Kirshenbaum (eds), lestrogens. Free Radic Biol Med 30: 62–73. Nova Science Publishers, New York (181–199). Turino GM, Cantor JO. (2003). Hyaluronan in respiratory injury and repair. Am Soltes L, Mendichi R, Kogan G, Mach M. (2004). Associating Hyaluronan De- J Respir Crit Care Med 167: 1169–1175. rivatives: A Novel Horizon in Viscosupplementation of Osteoarthritic Uthman I, Raynauld JP, Haraoui B. (2003). Intra-articular therapy in osteoar- Joints. Chem Biodivers 1: 468–472. thritis. Postgrad Med J 79: 449–453. Soltes L, Brezova V, Stankovska M, Kogan G, Gemeiner P. (2006a). Degrada- Valachova K, Vargova A, Rapta P, Hrabarova E, Drafi F, Bauerova K, Juranek tion of high-molecular-weight hyaluronan by hydrogen peroxide in the I, Soltes L. (2011). Aurothiomalate as preventive and chain-breaking anti- presence of cupric ions. Carbohydr Res 341: 639–644. oxidant in radical degradation of high-molar-mass hyaluronan. Chemistry Soltes L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. (2006b) & Biodiversity 8: 1274–1283. Degradative action of reactive oxygen species on hyaluronan. Biomacro- Valachova K, Banasova M, Machova L, Juranek I, Bezek S, Soltes L. (2013b). molecules 7: 659–668. Antioxidant activity of various hexahydropyridoindoles. Journal of Informa- Soltes L, Stankovska M, Brezova V, Schiller J, Arnhold J, Kogan G, Gemeiner P. tion Intelligence and Knowledge 5: 15–32. (2006c). Hyaluronan degradation by copper (II) chloride and ascorbate: ro- Valachova K, Hrabarova E, Priesolova E, Nagy M, Banasova M, Juranek I, Soltes tational viscometric, EPR spin-trapping, and MALDI-TOF mass spectromet- L. (2011). Free-radical degradation of high-molecular-weight hyaluronan in- ric investigations Carbohydr Res 341: 2826–2834. duced by ascorbate plus cupric ions. Testing of bucillamine and its SA981- Soltes L, Stankovska M, Kogan G, Germeiner P, Stern R. (2005). Contribution metabolite as antioxidants. J Pharma & Biomedical Analysis 56: 664–670. of oxidative reductive reations to high molecular weight hyaluronan ca- Valachová K, Hrabárová E, Dráfi F, Juránek I, Bauerová K, Priesolová E, Nagy tabolism. Chem Biodivers 2: 1242–1245. M, Šoltés L. (2010a). Ascorbate and Cu(II) induced oxidative degradation of Soltes L, Valachova K, Mendichi R, Kogan G, Arnhold J, Gemeiner P. (2007). high-molar-mass hyaluronan. Pro- and antioxidative eff ects of some thiols. Solution properties of high-molar-mass hyaluronans: the biopolymer deg- Neuroendocrinol Lett 31(2): 101–104. radation by ascorbate. Carbohydr Res 342: 1071–1077. Valachová K, Hrabárová E, Gemeiner P, Šoltés L. (2008). Study of pro- and Soltes L. (2010). Hyaluronan – A High-Molar-Mass Messenger Reporting on the anti-oxidative properties of d-penicillamine in a  system comprising high- Status of Synovial Joints: Part II. Pathophysiological Status In: “New Steps in molar-mass hyaluronan, ascorbate, and cupric ions. Neuroendocrinol Lett Chemical and Biochemical Physics. Pure and Applied Science” E. M. Pearce, 29: 697–701. G. Kirshenbaum, G. E. Zaikov (eds), Nova Science Publishers, New York pp. Valachová K, Hrabárová E, Juránek I, Šoltés L. (2011b). Radical degradation of 137–152. high-molar-mass hyaluronan induced by Weissberger oxidative system. Stankovska M, Arnhold J, Rychly J, Spalteholz H, Gemeiner P, Soltes L. (2007). Testing of thiol compounds in the function of antioxidants. 16th Interdisci- In vitro screening of the action of non-steroidal anti-infl ammatory drugs on plinary Slovak-Czech Toxicological Conference in Prague. Interdiscip Toxicol hypochlorous acid-induced hyaluronan degradation. Polym Degrad Stabil 4(2): 65. 92: 644–652. Valachová K, Kogan G, Gemeiner P, Šoltés L. (2008b). Hyaluronan degrada- Stankovska M, Soltes L, Vikar tovska A, Mendichi r, Lath D, Molnarova M, Gemei- tion by ascorbate: Protective eff ects of manganese (II). Cellulose Chem. ner P. (2004). Study of hyaluronan degradation by means of rotational Vis- Technol 42(9–10): 473−483. cometry: Contribution of the material of viscometer. Chem Pap 58: 348–352. Valachová K, Kogan G, Gemeiner P, Šoltés L. (2009b). Hyaluronan degrada- Stankovska M, Hrabarova E, Valachova K, Molnarova M, Gemeiner P, Soltes L. tion by ascorbate: protective eff ects of manganese (II) chloride. In: Progress in (2006). The degradative action of peroxynitrite on high-molecular-weight Chemistry and Biochemistry. Kinetics, Thermodynamics, Synthesis, Proper- hyaluronan . Neuroendocrinol Lett 27(Suppl. 2): 31–34. ties and Application, Nova Science Publishers, N.Y, Chapter 20, pp. 201–215. Stankovska M, Soltes L, Vikartovska A, Gemeiner P, Kogan G, Bakos D. (2005). Valachová K, Mendichi R, Šoltés L. (2010c). Eff ect of L-glutathione on high-mo- Degradation of high-molecular-weight hyaluronan: a rotational viscome- lar-mass hyaluronan degradation by oxidative system Cu(II) plus ascorbate. In: try study. Biologia 60(Suppl. 17): 149–152. Monomers, Oligomers, Polymers, Composites, and Nanocomposites, Ed: R. Stern R, Kogan G, Jedrzejas M. J, Soltes L. (2007). The many ways to cleave hy- A. Pethrick P. Petkov, A. Zlatarov G. E. Zaikov, S. K. Rakovsky, Nova Science aluronan. Biotechnol Adv 25: 537–557. Publishers, N.Y, Chapter 6, pp. 101–111. Stiebel-Kalish H, Gaton DD, Weinberger D. (1998). A comparison of the eff ect Valachová K, Rapta P, Kogan G, Hrabárová E, Gemeiner P, Šoltés L. (2009a). of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye 12: Degradation of high-molar-mass hyaluronan by ascorbate plus cupric ions: 829–833. eff ects of D-penicillamine addition. Chem Biodivers 6: 389–395. Suchanek E, Simunic V, Juretic D, Grizelj V. (1994). Follicular-fl uid contents of Valachová K, Rapta P, Slováková M, Priesolová E, Nagy M, Mislovičová D, Dráfi hyaluronic-acid, follicle-stimulating-hormone and steroids relative to the F, Bauerová K, Šoltés L. (2013a). Radical degradation of high-molar-mass hy- success of in-vitro fertilization of human oocytes. Fertil Steril 62: 347–352. aluronan induced by ascorbate plus cupric ions. Testing of arbutin in the func- Surendrakumar K, Martyn GP, Hodgers ECM. (2003). Sustained release of in- tion of antioxidant. In: Advances in Kinetics and Mechanism of Chemical Re- sulin from sodium hyaluronate based dry powder formulations after pul- actions, G. E. Zaikov, A. J. M. Valente, A. L. Iordanskii (eds), Apple Academic monary delivery to beagle dogs. J Control Release 91: 385–394. Press, Waretown, NJ, USA, pp. 1–19.  ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Valachová K, Šoltés L. (2010b). Eff ects of biogenic transition metal ions Zn(II) Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. (1992). Light microscopic characterization of the fi broblastlike synovial intimal cell (synoviocyte). Ar- and Mn(II) on hyaluronan degradation by action of ascorbate plus Cu(II) ions. thritis Rheum 35: 1179–1184. In: New Steps in Chemical and Biochemical Physics. Pure and Applied Sci- ence, Nova Science Publishers, Ed: E. M. Pearce, G. Kirshenbaum, G.E. Zai- Worrall JG, Bayliss MT, Edwards JC. (1991). Morphological localization of hyal- uronan in normal and diseased synovium. J Rheumatol 18: 1466–1472. kov, Nova Science Publishers, N.Y, Chapter 10, pp. 153–160. Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC. (1994). Zonal distribution of Valachová K, Vargová A, Rapta P, Hrabárová E, Dráfi F, Bauerová K, Juránek chondroitin-4-sulphate/ dermatan sulphate and chondroitin-6-sulphate in I, Šoltés L. (2011a). Aurothiomalate in function of preventive and chain- normal and diseased human synovium. Ann Rheum Dis 53: 35–38. breaking antioxidant at radical degradation of high-molar-mass hyaluro- Yerushalmi N, Arad A, Margalit R. (1994). Molecular and cellular studies of hy- nan. Chem Biodivers 8: 1274–1283. aluronic acid-modifi ed liposomes as bioadhesive carriers for topical drug- Vanos HC, Drogendijk AC, Fetter WPF. (1991). The infl uence of contamination delivery in wound-healing. Arch Biochem Biophys 313: 267–273. of culture-medium with hepatitis-B virus on the outcome of in vitro fertil- Yerushalmi N, Margalit R. (1998). Hyaluronic acid-modifi ed bioadhesive lipo- ization pregnancies. Am J Obstet Gynecol 165: 152–159. somes as local drug depots: eff ects of cellular and fl uid dynamics on lipo- Vazquez JR, Short B, Findlow AH. (2003). Outcomes of hyaluronan therapy in some retention at target sites. Arch Biochem Biophys 349: 21–26. diabetic foot wounds. Diabetes Res Clin Pract 59: 123–127. Yun YH, Goetz DJ, Yellen P, Chen W. (2004). Hyaluronan microspheres for sus- Weigel PH, Hascall VC, Tammi M. (1997). Hyaluronan synthases. J Biol Chem tained gene delivery and site-specifi c targetting. Biomaterials 25: 147–157. 272: 13997–14000. Zhu YX, Granick S. (2003). Biolubrication: hyaluronic acid and the infl uence West DC, Hampson IN, Arnold F, Kumar S. (1985). Angiogenesis induced by on its interfacial viscosity of an antiinfl ammatory drug. Macromolecules 36: 973–976. degradation products of hyaluronic acid. Science 228: 1324–1326. 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Hyaluronan and synovial joint: function, distribution and healing

Interdisciplinary Toxicology , Volume 6 (3) – Sep 1, 2013

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Interdiscip Toxicol. 2013; Vol. 6(3): 111–125. interdisciplinary doi: 10.2478/intox-2013-0019 Published online in: www.intertox.sav.sk & www.versita.com/it Copyright © 2013 SETOX & IEPT, SASc. This is an Open Access article distributed under the terms of the Creative Commons Attribu- tion License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. REVIEW ARTICLE Hyaluronan and synovial joint: function, distribution and healing 1,2 Tamer Mahmoud TAMER Polymer Materials Research Department, Advanced Technologies and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, Egypt Laboratory of Bioorganic Chemistry of Drugs, Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, Bratislava, Slovak Republic ITX060313R03 • Received: 18 July 2013 • Revised: 25 August 2013 • Accepted: 10 September 2013 ABSTRACT Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of hyaluronan causing several diseases related to joints. This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for using thiol compounds as antioxidants preventing HA degradations under inflammation conditions. KEY WORDS: synovial joint fluid; hyaluronan; antioxidant; thiol compound Introduction The human skeleton consists of both fused and individual Cartilage functions also as a shock absorber. This bones supported and supplemented by ligaments, tendons, property is derived from its high water entrapping capac- and skeletal muscles. Articular ligaments and tendons are ity as well as from the structure and intermolecular inter- the main parts holding together the joint(s). In respect of actions among polymeric components that constitute the movement, there are freely moveable, partially moveable, and immovable joints. Synovial joints (Figure 1), the freely moveable ones, allow for a large range of motion Synovium and encompass wrists, knees, ankles, shoulders, and hips Cartilage (Kogan, 2010). Structure of synovial joints Cartilage In a healthy synovial joint, heads of the bones are encased in a smooth (hyaline) cartilage layer. These tough slippery layers – e.g. those covering the bone ends in the knee joint – belong to mechanically highly stressed tissues in the human body. At walking, running, or sprinting the strokes frequency attain approximately 0.5, 2.5 or up to 10 Hz. Joint cavity with Ligament forming Correspondence address: synovial fluid joint capsule Dr. Tamer Mahmoud Tamer Polymer Materials Research Department, Advanced Technologies and New Materials Research Institute (ATNMRI), City of Scientific Research Figure 1. Normal, healthy synovial joint (adapted from Kogan, and Technological Applications (SRTA- City) 2010). New Borg El-Arab City 21934, Alexandria, Egypt. E-MAIL: ttamer85@gmail.com Hyaluronan and synovial joint Tamer Mahmoud Tamer cartilage tissue (Servaty et al., 2000). Figure 2 sketches pool through which nutrients and regulatory cytokines a section of the cartilage – a chondrocyte cell that per- traverse. SF contains molecules that provide low-friction manently restructures/rebuilds its extracellular matrix. and low-wear properties to articulating cartilage surfaces. Three classes of proteins exist in articular cartilage: col- Molecules postulated to play a key role in lubrication lagens (mostly type II collagen); proteoglycans (primarily alone or in combination, are proteoglycan 4 (PRG4) aggrecan); and other noncollagenous proteins (including (Swann et al., 1985) present in SF at a concentration of link protein, fibronectin, COMP – cartilage oligomeric 0.05–0.35 mg/ml (Schmid et al., 2001), hyaluronan (HA) matrix protein) and the smaller proteoglycans (biglycan, (Ogston & Stanier, 1953) at 1–4 mg/ml (Mazzucco et al., decorin, and fibromodulin). The interaction between 2004), and surface-active phospholipids (SAPL) (Schwarz highly negatively charged cartilage proteoglycans and & Hills, 1998) at 0.1 mg/ml (Mazzucco et al., 2004). type II collagen fibrils is responsible for the compressive Synoviocytes secrete PRG4 (Jay et al., 2000; Schumacher and tensile strength of the tissue, which resists applied et al., 1999) and are the major source of SAPL (Dobbie load in vivo. et al., 1995; Hills & Crawford, 2003; Schwarz & Hills, 1996), as well as HA (Haubeck et al., 1995; Momberger et Synovium/synovial membrane al., 2005) in SF. Other cells also secrete PRG4, including Each synovial joint is surrounded by a fibrous, highly vas- chondrocytes in the superficial layer of articular cartilage cular capsule/envelope called synovium, whose internal (Schmid et al., 2001b; Schumacher et al., 1994) and, to a surface layer is lined with a synovial membrane. Inside much lesser extent, cells in the meniscus (Schumacher et this membrane, type B synoviocytes (fibroblast-like cell al., 2005). lines) are localized/embedded. Their primary function is As a biochemical depot, SF is an ultra filtrate of blood to continuously extrude high-molar-mass hyaluronans plasma that is concentrated by virtue of its filtration (HAs) into synovial f luid. through the synovial membrane. The synovium is a thin lining (~50 μm in humans) comprised of tissue macro- Synovial fl uid phage A cells, fibroblast-like B cells (Athanasou & Quinn, The synovial fluid (SF) of natural joints normally func- 1991; Revell, 1989; Wilkinson et al., 1992), and fenes- tions as a biological lubricant as well as a biochemical trated capillaries (Knight & Levick, 1984). It is backed Link protein Aggrecan Hyaluronan Fibronectin Integrin COMP Biglycan Chondrocyte Decorin Type IX collagen Fibromodulin Type II collagen Figure 2. Articular cartilage main components and structure (adapted from Chen et al., 2006). ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) S–S Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central by a thicker layer (~100 μm) of loose connective tissue called the subsynovium (SUB) that includes an extensive NORMAL JOINT system of lymphatics for clearance of transported mol- Cartilage Tendon ecules. The cells in the synovium form a discontinuous Muscle layer separated by intercellular gaps of several microns in width (Knight & Levick, 1984; McDonald & Levick, 1988). The extracellular matrix in these gaps contains collagen types I, III, and V (Ashhurst et al., 1991; Rittig et al., 1992), hyaluronan (Worrall et al., 1991), chondroitin sulphate (Price et al., 1996; Worrall et al., 1994), biglycan and decorin proteoglycans (Coleman et al., 1998), and fibronectin (Poli et al., 2004). The synovial matrix pro- vides the permeable pathway through which exchange of molecules occurs (Levick, 1994), but also offers sufficient outflow resistance (Coleman et al., 1998; Scott et al., Synovium 1998) to retain large solutes of SF within the joint cavity. Joint Capsule Together, the appropriate ref lection of secreted lubricants Bone by the synovial membrane and the appropriate lubricant Synovial Fluid secretion by cells are necessary for development of a mechanically functional SF (Blewis et al., 2007). In the joint, HA plays an important role in the protec- tion of articular cartilage and the transport of nutrients to cartilage. In patients with rheumatoid arthritis (RA), Bone (Figure 3) it has been reported that HA acts as an anti JOINT AFFECTED BY inflammatory substance by inhibiting the adherence of RHEUMATOID ARTHRITIS immune complexes to neutrophils through the Fc receptor (Brandt, 1970), or by protecting the synovial tissues from Bone Loss/Erosion the attachment of inflammatory mediators (Miyazaki et al., 1983, Mendichi & Soltes, 2002). Cartilage Loss •– • Reactive oxygen species (ROS) (O , H O , OH) are 2 2 2 generated in abundance by synovial neutrophils from RA patients, as compared with synovial neutrophils of osteo- arthritis (OA) patients and peripheral neutrophils of both RA and OA patients (Niwa et al., 1983). McCord (1973) demonstrated that HA was susceptible to degradation by ROS in vitro, and that this could be protected by superoxide dismutase (SOD) and/or catalase, which suggests the possibility that there is pathologic oxidative damage to synovial fluid components in RA patients. Dahl et al. (1985) reported that there are reduced HA concentrations in synovial fluids from RA patients. It has also been reported that ROS scavengers inhibit the Inflamed Synovium degradation of HA by ROS (Soltes, 2010; Blake et al., 1981; Bone Loss Betts & Cleland, 1982; Soltes et al., 2004). (Generalized) Swollen Joint Capsule These findings appear to support the hypothesis that ROS are responsible for the accelerated degradation of HA in the rheumatoid joint. In the study of Juranek and Soltes (2012) the oxygen radical scavenging activities of synovial Figure 3. Normal, (healthy) and rheumatoid arthritis synovial joint. fluids from both RA and OA patients were assessed, and the antioxidant activities of these synovial fluids were analyzed by separately examining HA, d-glucuronic acid, and N-acetyl-d-glucosamine. contained two sugar molecules, one of which was uronic acid. For convenience, therefore, they proposed the name “hyaluronic acid”. The popular name is derived from Hyaluronan “hyalos”, which is the Greek word for glass + uronic acid (Meyer & Palmer, 1934). At the time, they did not know In 1934, Karl Meyer and his colleague John Palmer iso- that the substance which they had discovered would lated a previously unknown chemical substance from the prove to be one of the most interesting and useful natural vitreous body of cows’ eyes. They found that the substance macromolecules. HA was first used com mercially in 1942 Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer when Endre Balazs applied for a patent to use it as a substi- that hyaluronan separates most tissue surfaces that slide tute for egg white in bakery products (Necas et al., 2008). along each other. The extremely lubricious properties The term “hyaluronan” was introduced in 1986 to con- of hyaluronan have been shown to reduce postoperative form to the international nomenclature of polysaccharides adhesion forma tion following abdominal and orthopedic and is attributed to Endre Balazs (Balazs et al., 1986) who surgery. As mentioned, the polymer in solution assumes coined it to encompass the different forms the molecule a stiffened helical configuration, which can be at tributed can take, e.g, the acid form, hyaluronic acid, and the salts, to hydrogen bonding between the hydroxyl groups along such as sodium hyaluronate, which forms at physiological the chain. As a result, a coil structure is formed that traps pH (Laurent, 1989). HA was subsequently isolated from approximately 1000 times its weight in water (Chabrecek et many other sources and the physicochemi cal structure al., 1990; Cowman & Matsuoka, 2005; Schiller et al., 2011) properties and biological role of this polysaccharide were studied in numerous laborato ries (Kreil, 1995). This work has been summarized in a Ciba Foundation Symposium Properties of hyaluronan (Laurent, 1989) and a recent review (Laurent & Fraser, 1992; Chabrecek et al., 1990; Orvisky et al., 1992). Hyaluronan networks Hyaluronan (Figure 4) is a unique biopolymer com- The physico-chemical properties of hyaluronan were stud- posed of repeating disaccharide units formed by N-acetyl- ied in detail from 1950 onwards (Comper & Laurent, 1978). d-glucosamine and d-glucuronic acid. Both sugars are The molecules behave in solution as highly hydrated spatially related to glucose which in the β-configuration randomly kinked coils, which start to entangle at concen- allows all of its bulky groups (the hydroxyls, the carbox- trations of less than 1 mg/mL. The entanglement point ylate moiety, and the anomeric carbon on the adjacent can be seen both by sedimentation analysis (Laurent et sugar) to be in sterically favorable equatorial posi tions al., 1960) and viscosity (Morris et al., 1980). More recently while all of the small hydrogen atoms occupy the less Scott and his group have given evidence that the chains sterically favorable axial positions. Thus, the structure of when entangling also interact with each other and form the disaccharide is energetically very stable. HA is also stretches of double helices so that the network becomes unique in its size, reaching up to several million Daltons mechanically more firm (Scott et al., 1991). and is synthesized at the plasma membrane rather than in the Golgi, where sulfated glycosaminoglycans are added Rheological properties to protein cores (Itano & Kimata, 2002; Weigel et al., 1997; Solutions of hyaluronan are viscoelastic and the viscosity Kogan et al., 2007a). is markedly shearing dependent (Morris et al., 1980; Gibbs In a physiological solution, the backbone of a HA mol- et al., 1968). Above the entanglement point the viscosity ecule is stiffened by a combina tion of the chemical struc- increases rapidly and exponentially with concentration 3.3 ture of the disaccha ride, internal hydrogen bonds, and (~c ) (Morris et al., 1980) and a solution of 10 g/l may interactions with the solvent. The axial hydrogen atoms have a viscosity at low shear of ~10 times the viscosity of form a non-polar, relatively hydrophobic face while the the solvent. At high shear the viscosity may drop as much equatorial side chains form a more polar, hy drophilic face, as ~10 times (Gibbs et al., 1968). The elasticity of the thereby creating a twisting ribbon structure. Solutions of system increases with increasing molecular weight and hyaluronan manifest very unusual rheological properties concentration of hyaluronan as expected for a molecular and are exceedingly lubricious and very hydrophilic. In network. The rheological properties of hyaluronan have solution, the hyaluronan polymer chain takes on the been connected with lubrication of joints and tissues form of an expanded, random coil. These chains entangle and hyaluronan is commonly found in the body between with each other at very low concentrations, which may surfaces that move along each other, for example cartilage contribute to the unusual rheological proper ties. At surfaces and muscle bundles (Bothner & Wik, 1987). higher concentrations, solutions have an extremely high but shear-dependent viscosity. A 1% solution is like jelly, Water homeostasis but when it is put under pressure it moves easily and A fixed polysaccharide network offers a high resistance can be administered through a small-bore needle. It has to bulk flow of solvent (Comper & Laurent, 1978). This therefore been called a “pseudo-plastic” material. The was demonstrated by Day (1950) who showed that hyal- extraordi nary rheological properties of hyaluronan solu- uronidase treatment removes a strong hindrance to water f low through a fascia. Thus HA and other polysaccharides tions make them ideal as lubricants. There is evidence prevent excessive fluid fluxes through tissue compart- ments. Furthermore, the osmotic pressure of a hyaluronan O H C H O C O H 3 solution is non-ideal and increases exponentially with the O H N H O C H O H O O concentration. In spite of the high molecular weight of O O H O H O n N H O C O H the polymer the osmotic pressure of a 10 g/l hyaluronan C H O C O H 3 O H solution is of the same order as an l0 g/l albumin solu- tion. The exponential relationship makes hyaluronan Figure 4. Structural formula of hyaluronan – the acid form. and other polysaccharides excellent osmotic buffering substances – moderate changes in concentration lead ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central to marked changes in osmotic pressure. Flow resistance Medical applications of hyaluronic acid together with osmotic buffering makes hyaluronan an The viscoelastic matrix of HA can act as a strong bio- ideal regulator of the water homeostasis in the body. compatible support material and is therefore commonly used as growth scaffold in surgery, wound healing and Network interactions with other macromolecules embryology. In addition, administration of purified high The hyaluronan network retards the diffusion of other molecular weight HA into orthopaedic joints can restore molecules (Comper & Laurent, 1978; Simkovic et al., the desirable rheological properties and alleviate some of 2000). It can be shown that it is the steric hindrance which the symptoms of osteoarthritis (Balazs & Denlinger, 1993; restricts the movements and not the viscosity of the solu- Balazs & Denlinger, 1989; Kogan et al., 2007). The success tion. The larger the molecule the more it will be hindered. of the medical applications of HA has led to the produc- In vivo hyaluronan will therefore act as a diffusion barrier tion of several successful commercial products, which and regulate the transport of other substances through have been extensively reviewed previously. the intercellular spaces. Furthermore, the network will Table 1 summarizes both the medical applications and exclude a certain volume of solvent for other molecules; the commonly used commercial preparations containing the larger the molecule the less space will be available HA used within this field. HA has also been extensively to it (Comper & Laurent, 1978). A solution of 10 g/l of studied in ophthalmic, nasal and parenteral drug delivery. hyaluronan will exclude about half of the solvent to serum In addition, more novel applications including pulmonary, albumin. Hyaluronan and other polysaccharides therefore implantation and gene delivery have also been suggested. take part in the partition of plasma proteins between the Generally, HA is thought to act as either a mucoadhesive vascular and extravascular spaces. The excluded volume and retain the drug at its site of action/absorption or to phenomenon will also affect the solubility of other macro- modif y the in vivo release/absorption rate of the therapeu- molecules in the interstitium, change chemical equilibria tic agent. A summary of the drug delivery applications of and stabilize the structure of, for example, collagen fibers. HA is shown in Table 2. Table 1. Summary of the medical applications of hyaluronic acid (Brown & Jones, 2005). Disease state Applications Commercial products Publications Hochburg, 2000; Altman, 2000; Dougados, 2000; Guidolin et al., Hyalgan® (Fidia, Italy) 2001; Maheu et al., 2002; Barrett & Siviero, 2002; Miltner et al., Lubrication and mechanical Artz® (Seikagaku, Japan) 2002;Tascioglu and Oner, 2003; Uthman et al., 2003; Kelly et al., Osteoarthritis support for the joints ORTHOVISC® (Anika, USA) 2003; Hamburger et al., 2003; Kirwan, 2001; Ghosh & Guidolin, Healon®, Opegan® and Opelead® 2002; Mabuchi et al., 1999; Balazs, 2003; Fraser et al., 1993; Zhu & Granick, 2003. Ghosh & Jassal, 2002; Risbert, 1997; Inoue & Katakami, 1993; Implantation of artificial Surgery and Bionect®, Connettivina® Miyazaki et al., 1996; Stiebel-Kalish et al., 1998; Tani et al., 2002; intraocular lens, wound healing and Jossalind® Vazquez et al., 2003; Soldati et al., 1999; Ortonne, 1996; Cantor et viscoelastic gel al., 1998; Turino & Cantor, 2003. Simon et al., 2003; Gardner et al., 1999; Vanos et al., 1991; Kem- mann, 1998; Suchanek et al., 1994; Joly et al., 1992; Gardner, 2003; Culture media for the use of Embryo implantation EmbryoGlue® (Vitrolife, USA) Lane et al., 2003; Figueiredo et al., 2002, Miyano et al., 1994; Kano in vitro fertilization et al., 1998; Abeydeera, 2002; Jaakma et al., 1997; Furnus et al., 1998;Jang et al., 2003. Table 2. Summary of the drug delivery applications of hyaluronic acid. Route Justification Therapeutic agents Publications Jarvinen et al., 1995; Sasaki et al., 1996; Gurny et al., 1987; Camber et al., 1987; Camber & Edman, 1989; Increased ocular residence of drug, Pilocarpine, tropicamide, timolol, gen- Saettone et al., 1994; Saettone et al., 1991; Bucolo et al., 1998; Ophthalmic which can lead to increased timycin, tobramycin, Bucolo & Mangiafico, 1999; Herrero-Vanrell et al., 2000; Moreira bioavailability arecaidine polyester, (S) aceclidine et al., 1991; Bernatchez et al., 1993; Gandolfi et al., 1992; Langer et al., 1997. Bioadhesion resulting in increased Xylometazoline, vasopressin, Nasal Morimoto et al., 1991; Lim et al., 2002. bioavailability gentamycin Absorption enhancer Pulmonary Insulin Morimoto et al., 2001; Surendrakumar et al., 2003. and dissolution rate modification Drobnik, 1991; Sakurai et al., 1997; Luo and Prestwich, 1999; Luo Taxol, superoxide dismutase, Drug carrier and facilitator of liposo- et al., 2000; Prisell et al., 1992; Yerushalmi et al., 1994; Yerushalmi Parenteral human recombinant insulin-like mal entrapment & Margalit, 1998; Peer & Margalit, 2000; growth factor, doxorubicin Eliaz & Szoka, 2001; Peer et al., 2003. Implant Dissolution rate modification Insulin Surini et al., 2003; Takayama et al., 1990. Dissolution rate modification Gene Plasmid DNA/monoclonal antibodies Yun et al., 2004; Kim et al., 2003. and protection Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Cosmetic uses of hyaluronic acid result, the concentration of hyaluronan increases and a HA has been extensively utilized in cosmetic products gel structure of micrometric thickness is formed which because of its viscoelastic properties and excellent bio- protects the cartilage surfaces from frictional damage compatibility. Application of HA containing cosmetic (Hlavacek, 1993). This mechanism to form a protective products to the skin is reported to moisturize and restore layer is much less effective in arthritis when the synovial elasticity, thereby achieving an antiwrinkle effect, albeit hyaluronan has both a lower concentration and a lower so far no rigorous scientific proof exists to substantiate molecular weight than normal. Another change in the this claim. HA-based cosmetic formulations or sun- arthritic joint is the protein composition of the synovial screens may also be capable of protecting the skin against fluid. Fraser et al. (1972) showed more than 40 years ago ultraviolet irradiation due to the free radical scavenging that addition of various serum proteins to hyaluronan properties of HA (Manuskiatti & Maibach, 1996). substantially increased the viscosity and this has received HA, either in a stabilized form or in combination with a renewed interest in view of recently discovered hyalad- other polymers, is used as a component of commercial herins (see above). TSG-6 and inter-α-trypsin inhibitor dermal fillers (e.g. Hylaform®, Restylane® and Dermalive®) and other acute phase reactants such as haptoglobin are in cosmetic surgery. It is reported that injection of such concentrated to arthritic synovial fluid (Hutadilok et al., products into the dermis, can reduce facial lines and 1988). It is not known to what extent these are affecting wrinkles in the long term with fewer side-effects and the rheology and lubricating properties. better tolerability compared with the use of collagen (Duranti et al., 1998; Bergeret-Galley et al., 2001; Leyden Scavenger functions et al., 2003). The main side-effect may be an allergic reac- Hyaluronan has also been assigned scavenger functions tion, possibly due to impurities present in HA (Schartz, in the joints. It has been known since the 1940s that 1997; Glogau, 2000). hyaluronan is degraded by various oxidizing systems and ionizing irradiation and we know today that the common denominator is a chain cleavage induced by free Biological function of hyaluronan radicals, essentially hydroxy radicals (Myint et al., 1987). Through this reaction hyaluronan acts as a very efficient Naturally, hyaluronan has essential roles in body func- scavenger of free radicals. Whether this has any biological tions according to organ type in which it is distributed importance in protecting the joint against free radicals is (Laurent et al., 1996). unknown. The rapid turnover of hyaluronan in the joints has led to the suggestion that it also acts as a scavenger Space fi ller for cellular debris (Laurent et al., 1995). Cellular material The specific functions of hyaluronan in joints are still could be caught in the hyaluronan network and removed essentially unknown. The simplest explanation for its at the same rate as the polysaccharide (Stankovska et al., presence would be that a f low of hyaluronan through the 2007; Rapta, et al., 2009). joint is needed to keep the joint cavity open and thereby allow extended movements of the joint. Hyaluronan is Regulation of cellular activities constantly secreted into the joint and removed by the As discussed above, more recently proposed functions synovium. The total amount of hyaluronan in the joint of hyaluronan are based on its specific interactions with cavity is determined by these two processes. The half-life hyaladherins. One interesting aspect is the fact that hyal- of the polysaccharide at steady-state is in the order of uronan inf luences angiogenesis but the effect is different 0.5–1 day in rabbit and sheep (Brown et al., 1991; Fraser depending on its concentration and molecular weight et al., 1993). The volume of the cavity is determined by the (Sattar et al., 1992). High molecular weight and high pressure conditions (hydrostatic and osmotic) in the cav- concentrations of the polymer inhibit the formation of ity and its surroundings. Hyaluronan could, by its osmotic capillaries, while oligosaccharides can induce angiogen- contributions and its formation of flow barriers in the esis. There are also reports of hyaluronan receptors on limiting layers, be a regulator of the pressure and f low rate vascular endothelial cells by which hyaluronan could act (McDonald & Leviek, 1995). It is interesting that in fetal on the cells (Edwards et al., 1995). The avascularity of the development the formation of joint cavities is parallel with joint cavity could be a result of hyaluronan inhibition of a local increase in hyaluronan (Edwards et al., 1994). angiogenesis. Another interaction of some interest in the joint Lubrication is the binding of hyaluronan to cell surface proteins. Hyaluronan has been regarded as an ideal lubricant in Lymphocytes and other cells may find their way to joints the joints due to its shear-dependent viscosity (Ogston & through this interaction. Injection of high doses of hyal- Stanier, 1953) but its role in lubrication has been refuted uronan intra-articularly could attract cells expressing by others (Radin et al., 1970). However, there are now these proteins. Cells can also change their expression of reasons to believe that the function of hyaluronan is to hyaluronan-binding proteins in states of disease, whereby form a film between the cartilage surfaces. The load on hyaluronan may influence immunological reactions and the joints may press out water and low-molecular solutes cellular traffic in the path of physiological processes from the hyaluronan layer into the cartilage matrix. As a in cells (Edwards et al., 1995). The observation often ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central reported that intra-articular injections of hyaluronan f. Termination phase: quick formation of alkoxy- alleviate pain in joint disease (Adams, 1993) may indicate type C-fragments and the fragments with a termi- a direct or indirect interaction with pain receptors. nal C=O group due to the glycosidic bond scission of hyaluronan. Alkoxy-type C fragments may continue the propagation phase of the free-radical Hyaluronan and synovial fl uid hyaluronan degradation reaction. Both fragments are represented by reduced molar masses (Kogan, In normal/healthy joint, the synovial f luid, which consists 2011; Rychly et al., 2006; Hrabarova et al., 2012; of an ultrafiltrate of blood plasma and glycoproteins con- Surovcikova et al., 2012; Valachova et al., 2013b; tains HA macromolecules of molar mass ranging between Banasova et al., 2012). 6–10 mega Daltons (Praest et al., 1997). SF serves also as a Several thiol compounds have attracted much atten- lubricating and shock absorbing boundary layer between tion from pharmacologists because of their reactivity moving parts of synovial joints. SF reduces friction and toward endobiotics such as hydroxyl radical-derived spe- wear and tear of the synovial joint playing thus a vital role cies. Thiols play an important role as biological reductants in the lubrication and protection of the joint tissues from (antioxidants) preserving the redox status of cells and damage during motion (Oates et al., 2002). protecting tissues against damage caused by the elevated As SF of healthy humans exhibits no activity of reactive oxygen/nitrogen species (ROS/RNS) levels, by hyaluronidase, it has been inferred that oxygen-derived which oxidative stress might be indicated. free radicals are involved in a self-perpetuating process Soltes and his coworkers examined the effect of sev- of HA catabolism within the joint (Grootveld et al., eral thiol compounds on inhibition of the degradation 1991; Stankovska et al., 2006; Rychly et al., 2006). This kinetics of a high-molecular-weight HA in vitro. High radical-mediated process is considered to account for ca. molecular weight hyaluronan samples were exposed twelve-hour half-life of native HA macromolecules in SF. to free-radical chain degradation reactions induced by Acceleration of degradation of high-molecular-weight ascorbate in the presence of Cu(II) ions, the so called HA occurring under inflammation and/or oxidative stress is accompanied by impairment and loss of its visco- elastic properties (Parsons et al., 2002; Soltes et al., 2005; Ac H OH Stankovska et al., 2005; Lath et al., 2005; Hrabarova et al., OH NH COOH C C C O HO O O HO 2007; Valachova & Soltes, 2010; Valachova et al., 2013a). O O HO HO HOOC OH NH Low-molecular weight HA was found to exert different OH Ac H O 2 OH biological activities compared to the native high-molecu- lar-weight biopolymer. HA chains of 25–50 disaccharide Ac H OH COOH OH NH C C C O units are inf lammatory, immune-stimulatory, and highly HO O O HO O O HO HO angiogenic. HA fragments of this size appear to func- O OH HOOC NH OH Ac tion as endogenous danger signals, reflecting tissues 2 under stress (Noble, 2002; West et al., 1985; Soltes et al., 2007; Stern et al., 2007; Soltes & Kogan, 2009). Figure 5 Ac OH NH COOH OH C O describes the fragmentation mechanism of HA under free C C C HO O O HO O O HO radical stress. HO HOOC OH NH OH Ac A HA a. Initiation phase: the intact hyaluronan macromol- ecule entering the reaction with the HO radical HO Ac H OH formed via the Fenton-like reaction: NH COOH OH C C C C HO O O HO + 2+ • – Cu + H O  Cu + HO + OH O O 2 2 HO HO O O HOOC OH NH H O has its origin due to the oxidative action of OH Ac 2 2 II I Cu Cu the Weissberger system (see Figure 6) OH b. Formation of an alkyl radical (C-centered hyal- • H Ac OH uronan macroradical) initiated by the HO radical NH COOH OH C O C C C HO O O HO attack. O O HO HO c. Propagation phase: formation of a peroxy-type HOOC OH NH OH Ac C-macroradical of hyaluronan in a process of oxygenation after entrapping a molecule of O . Ac H OH d. Formation of a hyaluronan-derived hydroper- OH NH COOH C C C C O HO O O HO oxide via the reaction with another hyaluronan O O H O HO 2 O O HOOC OH NH macromolecule. OH Ac e. Formation of highly unstable alkoxy-type C-macroradical of hyaluronan on undergoing Figure 5. Schematic degradation of HA under free radical stress a redox reaction with a transition metal ion in a (Hrabarova et al., 2012). reduced state. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Weissberger’s oxidative system. The concentrations of l-Glutathione (GSH; l-γ-glutamyl-l-cysteinyl-glycine; both reactants [ascorbate, Cu(II)] were comparable to a ubiquitous endogenous thiol, maintains the intracel- those that may occur during an early stage of the acute lular reduction-oxidation (redox) balance and regulates phase of joint inflammation (see Figure 6) (Banasova et signaling pathways during oxidative stress/conditions. al., 2011; Valachova et al., 2011; Soltes et al., 2006a; Soltes GSH is mainly cytosolic in the concentration range of et al., 2006b; Stankovska et al., 2004; Soltes et al., 2006c; ca. 1–10 mM; however, in the plasma as well as in SF, the Soltes et al., 2007; Valachova et al., 2008; 2009; 2010; 2011; range is only 1–3 μM (Haddad & Harb, 2005). This unique 2013; Hrabarova et al., 2009, 2011; Rapta et al., 2009; 2010; thiol plays a crucial role in antioxidant defense, nutrient Surovcikova-Machova et al., 2012; Banasova et al., 2011; metabolism, and in regulation of pathways essential for Drafi et al., 2010; Fisher & Naughton, 2005). the whole body homeostasis. Depletion of GSH results in Figure 7 illustrates the dynamic viscosity of hyaluro- an increased vulnerability of the cells to oxidative stress nan solution in the presence and absence of bucillamine, (Hultberg & Hultberg, 2006). d-penicillamine and l-cysteine as inhibitors for free radi- It was found that l-glutathione exhibited the most cal degradation of HA. The study showed that bucillamine significant protective and chain-breaking antioxidative to be both a preventive and chain-breaking antioxidant. effect against hyaluronan degradation. Thiol antioxida- On the other hand, d-penicillamine and l-cysteine dose tive activity, in general, can be inf luenced by many factors dependently act as scavenger of OH radicals within the such as various molecule geometry, type of functional first 60 min. Then, however, the inhibition activity is lost groups, radical attack accessibility, redox potential, thiol and degradation of hyaluronan takes place (Valachova et al., concentration and pK , pH, ionic strength of solution, as 2011; Valachova et al., 2009; 2010; Hrabarova et al., 2009). well as different ability to interact with transition metals (Hrabarova et al., 2012). Figure 8 shows the dynamic viscosity versus time profiles of HA solution stressed to degradation with Weissberger’s oxidative system. As evident, addition of different concentrations of GSH resulted in a marked pro- H H O O tection of the HA macromolecules against degradation. + Cu(II) + O O Cu (I) The greater the GSH concentration used, the longer was O O CH OH 2 CH OH the observed stationary interval in the sample viscosity CH OH 2 CH OH values. At the lowest GSH concentration used, i.e. 1.0 μM (Figure 8), the time-dependent course of the HA degrada- tion was more rapid than that of the reference experiment with the zero thiol concentration. Thus, one could classif y O O + H GSH traces as functioning as a pro-oxidant. + Cu(II) + H O O Cu (I) 2 2 O The effectiveness of antioxidant activity of 1,4-dithio- CH OH CH OH erythritol expressed as the radical scavenging capacity was CH OH 2 CH OH studied by a rotational viscometry method (Hrabarova et al., 2010). 1,4-dithioerythritol, widely accepted and used as an effective antioxidant in the field of enzyme and Figure 6. Scheme. Generation of H O by Weissberger’s system 2 2 protein oxidation, is a new potential antioxidant standard from ascorbate and Cu(II) ions under aerobic conditions (Vala- exhibiting very good solubility in a variety of solvents. chova et al., 2011) Figure 9 describes the effect of 1,4-dithioerythritol on 10 10 100 50 6 6 4 4 AB C 060 120 180 240 300 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Time [min] Figure 7. Eff ect of A) L-penicillamine, B) L-cysteine and C) bucillamine with diff erent concentrations (50, 100 μM) on HA degradation induced by the oxidative system containing 1.0 μM CuCl + 100 μM ascorbic acid (Valachova et al., 2011). ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Dynamic viscosity [mPa·s] Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central 11 11 10 10 3 4 5 1 9 9 8 8 OH 7 0 7 SH 6 6 HS 5 5 OH 4 4 0 60 120 180 240 300 0 60 120 180 240 300 Time [min] Time [min] Figure 8. Comparison of the eff ect of L-glutathione on HA deg- radation induced by the system containing 1.0 μM CuCl plus 100 μM L-ascorbic acid. Concentration of L-glutathione in μM: Figure 9. Eff ect of 1,4-dithioerythritol (1) on HA degradation 1–1.0; 2–10; 3, 4, 5–50, 100, and 200. Concentration of reference induced by Weissberger’s oxidative system (0) (Hrabarova et al., experiment: 0–nil thiol concentration (Hrabarova et al., 2009; 2010). Valachova et al., 2010a). AB 6 6 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Figure 10. Evaluation of antioxidative eff ects of N-acetyl-L-cysteine against high-molar-mass hyaluronan degradation in vitro induced by Weissberger´s oxidative system. Reference sample (black): 1 μM Cu(II) ions plus 100 μM ascorbic acid; nil thiol concentration. N-Acetyl-L- cysteine addition at the onset of the reaction (A) and after 1 h (B) (25, 50,100 μM). (Hrabarova et al., 2012). degradation of HA solution under free radical stress Investigation of the antioxidative effect of N-Acetyl- (Hrabarova et al., 2010). l-cysteine. Unlike l-glutathione, N-acetyl-l-cysteine was N-Acetyl-l-cysteine (NAC), another significant pre- found to have preferential tendency to reduce Cu(II) ions to cursor of the GSH biosynthesis, has broadly been used as Cu(I), forming N-acetyl-l-cysteinyl radical that may sub- •– effective antioxidant in a form of nutritional supplement sequently react with molecular O to give O (Soloveva et 2 2 (Soloveva et al., 2007; Thibodeau et al., 2001). At low con- al., 2007; Thibodeau et al., 2001). Contrary to l-cysteine, centrations, it is a powerful protector of α -antiproteinase NAC (25 and 50 μM), when added at the beginning of the against the enzyme inactivation by HOCl. NAC reacts reaction, exhibited a clear antioxidative effect within ca. 60 with HO radicals and slowly with H O ; however, no and 80 min, respectively (Figure 10A). Subsequently, NAC 2 2 reaction of this endobiotic with superoxide anion radical exerted a modest pro-oxidative effect, more profound was detected (Aruoma et al., 1989). at 25-μM than at 100-μM concentration (Figure  10A). Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Dynamic viscosity [mPa·s] Dynamic viscosity [mPa·s] Dynamic viscosity [mPa·s] Hyaluronan and synovial joint Tamer Mahmoud Tamer AB 060 120 180 240 300 060 120 180 240 300 Time [min] Time [min] Figure 11. Evaluation of antioxidative eff ects of cysteamine against high-molar-mass hyaluronan degradation in vitro induced by Weissberger´s oxidative system. Reference sample (black): 1 mM CuII ions plus 100 μM ascorbic acid; nil thiol concentration. Cysteamine addition at the onset of the reaction (a) and after 1 h (b) (25, 50,100 μM). (Hrabarova et al., 2012). Adams ME. (1993). Viseosupplementation: A treatment for osteoarthritis. J Application of NAC 1 h after the onset of the reaction Rheumatol 20: Suppl. 39: 1–24. (Figure 10B) revealed its partial inhibitory effect against Altman RD. (2000). Intra-articular sodium hyaluronate in osteoarthritis of the formation of the peroxy-type radicals, independently knee. Semin Arthritis Rheum 30: 11–18. from the concentration applied (Hrabarova et al., 2012). Aruoma OI, Halliwell B, Hoey BM, Butler J. (1989). The antioxidant action of An endogenous amine, cysteamine (CAM) is a cystine- N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, su- depleting compound with antioxidative and anti-inflam- peroxide, and hypochlorous acid. Free Radic Biol Med 6: 593. matory properties; it is used for treatment of cystinosis – a Ashhurst DE, Bland YS, Levick JR. (1991). An immunohistochemical study of metabolic disorder caused by deficiency of the lysosomal the collagens of rabbit synovial interstitium. J Rheumatol 18: 1669–1672. cystine carrier. CAM is widely distributed in organisms Athanasou NA, Quinn J. (1991). Immunocytochemical analysis of human sy- novial lining cells: phenotypic relation to other marrow derived cells. Ann and considered to be a key regulator of essential metabolic Rheum Dis 50: 311–315. pathways (Kessler et al., 2008). Balazs EA, Denlinger JL. (1989). Clinical uses of hyaluronan. Ciba Found Symp Investigation of the antioxidative effect of cysteamine. 143: 265–280. Cysteamine (100 μM), when added before the onset of the Balazs EA, Laurent TC, Jeanloz RW. (1986). Nomencla ture of hyaluronic acid. reaction, exhibited an antioxidative effect very similar to Biochemical Journal 235: 903. that of GSH (Figure 8A and Figure 11A). Moreover, the Balazs EA. (2003). Analgesic eff ect of elastoviscous hyaluronan solutions and same may be concluded when applied 1 h after the onset the treatment of arthritic pain. Cells Tissues Organs 174: 49–62. of the reaction (Figure 11B) at the two concentrations (50 Balazs EA, Denlinger JL. (1993). Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol 20: 3–9. and 100 μM), suggesting that CAM may be an excellent Banasova M, Valachova K, Juranek I, Soltes L. (2012). Eff ect of thiol com- scavenger of peroxy radicals generated during the peroxi- pounds on oxidative degradation of high molar hyaluronan in vitro. Inter- dative degradation of HA (Hrabarova et al., 2012). discip Toxicol 5(Suppl. 1): 25–26. Banasova M, Valachova K, Juranek I, Soltes L. (2013b). Aloevera and methyl- sulfonylmethane as dietary supplements: Their potential benefi ts for ar- Acknowledgements thritic patients with diabetic complications. Journal of Information Intelli- gence and Knowledge 5: 51–68. Banasova M, Valachova K, Rychly J, Priesolova E, Nagy M, Juranek I, Soltes L. The author would like to thank the Institute of (2011). Scavenging and chain breaking activity of bucillamine on free-rad- Experimental Pharmacology & Toxicology for having ical mediated degradation of high molar mass hyaluronan. ChemZi 7: 205– invited him and oriented him in the field of medical research. He would also like to thank Slovak Academic Baňasová M, Valachová K, Hrabárová E, Priesolová E, Nagy M, Juránek I, Information Agency (SAIA) for funding him during his Šoltés L. (2011). Early stage of the acute phase of joint infl ammation. In vitro testing of bucillamine and its oxidized metabolite SA981 in the function of work in the Institute. antioxidants. 16th Interdisciplinary Czech-Slovak Toxicological Conference in Prague. Interdiscip Toxicol 4(2): 22. Barrett J P, Siviero P. (2002). Retrospective study of outcomes in Hyalgan(R)- treated patients with osteoarthritis of the knee. Clin Drug Invest 22: 87–97. REFERENCES Bergeret-Galley C, Latouche X, Illouz Y G.(2001). The value of a new fi ller ma- Abeydeera LR. (2002). In vitro production of embryos in swine. Theriogenol- terial in corrective and cosmetic surgery: DermaLive and DermaDeep. Aes- ogy 57: 257–273. thetic Plast Surg 25: 249–255. ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Dynamic viscosity [mPa·s] Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Bernatchez SF, Tabatabay C, Gurny R. (1993). Sodium hyaluronate 0.25-per- Edwards JCW (1995). Consensus statement. Second international meeting cent used as a vehicle increases the bioavailability of topically adminis- on synovium. Cell biology, physiology and pathology. Ann Rheum Dis 54: tered gentamicin. Graefes Arch Clin Exp Ophthalmol 231: 157–161. 389–91. Betts WH, Cleland LG. (1982): Eff ect of metal chelators and antiinfl ammatory Eliaz RE, Szoka FC. (2001). Liposome-encapsulated doxorubicin targeted to drugs on the degradation of hyaluronic acid. Arthritis Rheum 25: 1469–1476. CD44: a strategy to kill CD44-overexpressing tumor cells. Cancer Res 61: 2592–2601. Blake DR, Hall ND, Treby DA. (1981). Protection against superoxide and hy- drogen peroxide in synovial fl uid from rheumatoid patients. Clin Sci 61: Figueiredo F, Jones GM, Thouas GA, Trounson AO. (2002). The eff ect of extra- 483–486. cellular matrix molecules on mouse preimplantation embryo development in vitro. Reprod Fertil Dev 14: 443–451. Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. (2007). A model of synovial fl uid lubricant composition in normal and injured. Euro- Fisher AE, Naughton ODP. (2005). Therapeutic chelators for the twenty fi rst pean cells and materials 13: 26–39. century: new treatments for iron and copper mediated infl ammatory and neurological disorders. Curr Drug Delivery 2: 261–268. Bothner H, Wik O. (1987). Rheology of hyaluronate. Acta Otolaryngol Suppl 442: 25–30. Fraser JRE, Foo WK, Maritz JS. (1972). Viscous interactions of hyaluronic acid with some proteins and neutral saccharides. Ann Rheum Dis 31: 513–20. Brandt K. (1970). Modifi cation of chemotaxis by synovial fl uid hyaluronate. Arthritis Rheum 13: 308–309. Fraser JRE, Kimpton WG, Pierscionek BK, Cahill RNP. (1993). The kinetics of hyaluronan in normal and acutely infl amed synovial joints – observations Brown MB, Jones SA. (2005). Hyaluronic acid: a unique topical vehicle for with experimental arthritis in sheep. Semin Arthritis Rheum 22: 9–17. the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol 19: 308–318. Furnus CC, de Matos DG, Mar tinez AG. (1998). Eff ec t of hyaluronic acid on devel- opment of in vitro produced bovine embryos. Theriogenology 49: 1489–99. Brown TJ, Laurent UBG, Fraser JRE. (1991). Turnover of hyaluronan in synovial joints: elimination of labelled hyaluronan from the knee joints of the rab- Gandolfi SA, Massari A, Orsoni JG. (1992). Low-molecular-weight sodium hy- bit. Exp Physiol 76: 125–34. aluronate in the treatment of bacterial corneal ulcers. Graefes Arch Clin Exp Ophthalmol 230: 20–23. Bucolo C, Mangiafi co P. (1999). Pharmacological profi le of a new topical pilo- carpine formulation. J Ocul Pharmacol Ther 15: 567–573. Gardner DK, Lane M, Stevens J, Schoolcraft WB. (2003). Changing the start temperature and cooling rate in a slow-freezing protocol increases human Bucolo C, Spadaro A, Mangiafi co S. (1998). Pharmacological evaluation of a new timolol/pilocarpine formulation. Ophthalmic Res 30: 101–106. blastocyst viability. Fertil Steril 79: 407–410. Gardner DK, Rodriegez-Martinez H, Lane M. (1999). Fetal development after Camber O, Edman P, Gurny R. (1987). Infl uence of sodium hyaluronate on the meiotic eff ect of pilocarpine in rabbits. Curr Eye Res 6: 779–784. transfer is increased by replacing protein with the glycosaminoglycan hyal- uronan for mouse embryo culture and transfer. Hum Reprod 14: 2575–2580. Camber O, Edman P. (1989). Sodium hyaluronate as an ophthalmic vehicle – some factors governing its eff ect on the ocular absorption of pilocarpine. Ghosh P, Guidolin D. (2002). Potential mechanism of action of intraarticular hyaluronan therapy in osteoarthritis: are the eff ects molecular weight de- Curr Eye Res 8: 563–567. pendent? Semin Arthritis Rheum 32: 10–37. Cantor JO, Cerreta JM, Armand G, Turino GM. (1998). Aerosolized hyaluronic Ghosh S, Jassal M. (2002). Use of polysaccharide fi bres for modem wound acid decreases alveolar injury induced by human neutrophil elastase. Proc Soc Exp Biol Med 217: 471–475. dressings. Indian J Fibre Textile Res 27: 434–450. Chabrecek P, Soltes L, Kallay Z, Fugedi A. (1990). Isolation and characteriza- Gibbs DA, Merrill EW, Smith KA, Balazs EA. (1968). Rheology of hyaluronic tion of high molecular weight (3H) hyaluronic acid. J Label Compd Radio- acid. Biopolymers 6: 777–91. pharm 28: 1121–1125. Glogau RG. (2000). The risk of progression to invasive disease. J Am Acad Der- Chabrecek P, Soltes L, Kallay Z, Novak I. (1990). Gel permeation chromato- matol 42: S23–S24. graphic characterization of sodium hyaluronate and its reactions prepared Grootveld M, Henderson EB, Farrell A, Blake DR, Parkes HG, Haycock P. (1991). by ultrasonic degradation. Chromatographia 30: 201–204. Oxidative damage to hyaluronate and glucose in synovial fl uid during ex- Chen FH, Rousche KT, Tuan RS. (2006). Technology Insight: adult stem cells ercise of the infl amed rheumatoid joint. Detection of abnormal low-mo- in cartilage regeneration and tissue engineering. Nat Clin Pract Rheumatol lecular-mass metabolites by proton-N.M.R. spectroscopy. Biochem J 273: 2(7): 373–82. 459–467. Coleman P, Kavanagh E, Mason RM, Levick JR, Ashhurst DE. (1998). The pro- Guidolin DD, Ronchetti IP, Lini E. (2001). Morphological analysis of articular teoglycans and glycosaminoglycan chains of rabbit synovium. Histochem cartilage biopsies from a randomized. clinical study comparing the eff ects J 30: 519–524. of 500–730 kDa sodium hyaluronate Hyalgan(R) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage 9: Comper WD, Laurent TC. (1978). Physiological function of connective tissue 371–381. polysaccharidcs. Physiol Rev 58: 255–315. Gurny R, Ibrahim H, Aebi A. (1987). Design and evaluation of controlled re- Cowman MK, Matsuoka S. (2005). Experimental ap proaches to hyaluronan lease systems for the eye. J Control Release 6: 367–373. structure. Carbohydrate Re search 340: 791–809. Haddad JJ, Harb HL. (2005). L-gamma-Glutamyl-L-cysteinyl-glycine (glutathi- Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K. (1985). Concentration and one; GSH) and GSH-related enzymes in the regulation of pro- and anti-in- molecular weight of sodium hyaluronate in synovial fl uid from patients with fl ammatory cytokines: a signaling transcriptional scenario for redox(y) im- rheumatoid arthritis and other arthropathies. Ann Rheum Dis 44: 817–822. munologic sensor(s). Mol Immunol 42: 987–1014. Dobbie JW, Hind C, Meijers P, Bodart C, Tasiaux N, Perret J, Anderson JD. Hamburger MI, Lakhanpal S, Mooar PA, Oster D. (2003). Intra-articular hyal- (1995). Lamellar body secretion: ultrastructural analysis of an unexplored uronans: a review of product-specifi c safety profi les. Semin Arthritis Rheum function of synoviocytes. Br J Rheumatol 34: 13–23. 32: 296–309. Dougados M. (2000). Sodium hyaluronate therapy in osteoarthritis: argu- Haubeck HD, Kock R, Fischer DC, van de Leur E, Hoff meister K, Greiling H. ments for a potential benefi cial structural eff ect. Semin Arthritis Rheum 30: (1995). Transforming growth factor ß1, a major stimulator of hyaluronan 19–25. synthesis in human synovial lining cells. Arthritis Rheum 38: 669–677. Dráfi F, Valachová K, Hrabárová E, Juránek I, Bauerová K, Šoltés L. (2010). Herrero-Vanrell R, Fernandez-Carballido A, Frutos G, Cadorniga R. (2000). En- Study of methotrexate and β-alanyl-L-histidine in comparison with L-glu- tathione on high-molar-mass hyaluronan degradation induced by ascor- hancement of the mydriatic response to tropicamide by bioadhesive poly- mers. J Ocul Pharmacol Ther 16: 419–428. bate plus Cu (II) ions via rotational viscometry. 60th Pharmacological Days in Hradec Králové. Acta Medica 53(3): 170. Hills BA, Crawford RW. (2003) Normal and prosthetic synovial joints are lu- bricated by surface-active phospholipid: a hypothesis. J Arthroplasty 18: Drobnik J. (1991). Hyaluronan in drug delivery. Adv Drug Dev Rev 7: 295–308. 499–505. Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. (1998). Injectable hyal- Hlavacek M. (1993). The role of synovial fl uid fi ltration by cartilage in lubrica- uronic acid gel for soft tissue augmentation – a clinical and histological study. Dermatol Surg 24: 1317–1325. tion of synovial joints. J Biomech 26(10): 1145–50. Edwards JCW, Wilkinson LS, Jones HM. (1994). The formation of human syno- Hochberg MC. (2000). Role of intra-articular hyaluronic acid preparations in vial cavities: a possible role for hyaluronan and CD44 in altered interzone medical management of osteoarthritis of the knee. Semin Arthritis Rheum cohesion. J Anat 185: 355–67. 30: 2–10. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Hrabarova E, Valachova K, Rapta P, Soltes L. (2010). An alternative standard Knight AD, Levick JR. (1984). Morphometry of the ultrastructure of the blood- for trolox-equivalent antioxidant-capacity estimation based on thiol an- joint barrier in the rabbit knee. Q J Exp Physiol 69: 271–288. tioxidants. Comparative 2,2’-azinobis[3-ethylbenzothiazoline-6-sulfonic Kogan G. (2010). Hyaluronan – A High Molar mass messenger reporting on the acid] decolorization and rotational viscometry study regarding hyaluronan status of synovial joints: part 1. Physiological status In: New Steps in Chemical degradation. Chemistry & Biodiversity 7(9): 2191–2200. and Biochemical Physics. ISBN: 97 8-1-61668-923 -0. pp. 121–133. Hrabarova E, Valachova K, Rychly J, Rapta P, Sasinkova V, Malikova M, Soltes L. Kogan G, Soltes L, Stern R, Mendichi R. (2007a). Hyaluronic acid: A biopoly- (2009). High-molar-mass hyaluronan degradation by Weissberger’s system: mer with versatile physico-chemical and biological properties. Chapter 31 – Pro- and anti-oxidative eff ects of some thiol compounds. Polymer Degrada- in: Handbook of Polymer Research: Monomers, Oligomers, Polymers and tion and Stability 94: 1867–1875. Composites. Pethrick R. A, Ballada A, Zaikov G. E. (eds.), Nova Science Pub- Hrabarova E, Valachova K, Juranek I, Soltes L. (2012). Free-radical degrada- lishers, New York, pp. 393–439. tion of high-molar-mass hyaluronan induced by ascorbate plus cupric ions: Kogan G, Soltes L, Stern R, Gemeiner P. (2007). Hyaluronic acid: A natural bio- evaluation of antioxidative eff ect of cysteine-derived compounds. Chemis- polymer with a broad range of biomedical and industrial applications. Bio- try & Biodiversity 9: 309–317. technol Lett 29: 17–25. Hrabarova E, Gemeiner P, Soltes L. (2007). Peroxynitrite: In vivo and in vitro Kreil G. (1995). Hyaluronidases-A group of neglected enzymes. Protein Sci- synthesis and oxidant degradative action on biological systems regarding ences 4: 1666–1669. biomolecular injury and infl ammatory processes. Chem Pap 61: 417–437. Lane M, Maybach JM, Hooper K. (2003). Cryo-survival and development of Hrabárová E, Valachová K, Juránek I, Šoltés L. (2011). Free-radical degradation bovine blastocysts are enhanced by culture with recombinant albumin of high-molar-mass hyaluronan induced by ascorbate plus cupric ions. Anti- and hyaluronan. Mol Reprod Dev 64: 70–78. oxidative properties of the Piešťany-spa curative waters from healing peloid and maturation pool. In: “Kinetics, Catalysis and Mechanism of Chemical Re- Langer K, Mutschler E, Lambrecht G. (1997). Methylmethacrylate sulfopropyl- actions” G. E. Zaikov (eds), Nova Science Publishers, New York, pp. 29–36. methacrylate copolymer nanoparticles for drug delivery – Part III. Evalua- tion as drug delivery system for ophthalmic applications. Int J Pharm 158: Hrabárová E, Valachová K, Rychlý J, Rapta P, Sasinková V, Gemeiner P, Šoltés 219–231. L. (2009). High-molar-mass hyaluronan degradation by the Weissberger´s system: pro- and antioxidative eff ects of some thiol compounds. Polym De- Lath D, Csomorova K, Kollarikova G, Stankovska M, Soltes L. (2005). Molar grad Stab 94: 1867–1875. mass-intrinsic viscosity relationship of high-molar-mass yaluronans: In- volvement of shear rate. Chem Pap 59: 291–293. Hultberg M, Hultberg B. (2006). The eff ect of diff erent antioxidants on glu- tathione turnover in human cell lines and their interaction with hydrogen Laurent TC, Laurent UBG, Fraser JRE. (1996). The structure and function of hy- peroxide. Chem Biol Interact 163(3): 192–198. aluronan: An over view. Immunology and Cell Biology 74: A1–A7. Hutadilok N. Ghosh P, Brooks PM. (1988). Binding of haptoglobin. inter-α- Laurent TC. (1989). The biology of hyaluronan. In: Ciba Foundation Sympo- trypsin inhibitor, and l proteinase inhibitor to synovial fl uid hyaluronate sium. John Wiley and Sons, New York. 143: 1–298. and the infl uence of these proteins on its degradation byoxygen derived Laurent TC, Fraser JRE. (1992). Hyaluronan. FASEB J 6: 2397–2404. free radicals. Ann Rheum Dis 47: 377–85. Laurent TC. Laurent UBG, Fraser JRE. (1995). Functions of hyaluronan. Ann Inoue M, Katakami C. (1993). The eff ect of hyaluronic-acid on corneal epithe- Rheum Dis 54: 429–32. lial-cell proliferation. Invest Ophthalmol Vis Sci 34: 2313–2315. Laurent TC, Ryan M, Pictruszkiewicz A. (1960). Fractionation of hyaluronic Itano N, Kimata K. (2002). Mammalian hyaluronan synthases. IUBMB Life 54: acid. The polydispersity of hyaluronic acid from the vitreous body. Biochim 195–199. Biophys Acta 42: 476–85. Jaakma U, Zhang B R, Larsson B. (1997). Eff ects of sperm treatments on the in Levick JR. (1994). An analysis of the interaction between interstitial plasma vitro development of bovine oocytes in semidefi ned and defi ned media. protein, interstitial fl ow, and fenestral fi ltration and its application to Theriogenology 48: 711–720. synovium. Microvasc Res 47: 90–125. Jang G, Lee BC, Kang SK, Hwang WS. (2003). Eff ect of glycosaminoglycans on the preimplantation development of embryos derived from in vitro fertil- Leyden J, Narins RS, Brandt F. (2003). A randomized, double-blind, multi- ization and somatic cell nuclear transfer. Reprod Fertil Dev 15: 179–185. center comparison of the effi cacy and tolerability of Restylane versus Zy- plast for the correction of nasolabial folds. Dermatol Surg 29: 588–595. Jarvinen K, Jarvinen T, Urtti A. (1995). Ocular absorption following topical de- livery. Adv Drug Dev Rev 16: 3–19. Lim ST, Forbes B, Berry DJ, Martin GP, Brown MB. (2002). In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal Jay GD, Britt DE, Cha DJ. (2000). Lubricin is a product of megakaryocyte stim- delivery of gentamicin in rabbits. Int J Pharm 231: 73–82. ulating factor gene expression by human synovial fi broblasts. J Rheumatol 27: 594–600. Luo Y, Prestwich GD. (1999). Synthesis and selective cytotoxicity of a hyal- uronic acid-antitumor bioconjugate. Bioconjug Chem 10: 755–763. Joly T, Nibart M, Thibier M. (1992). Hyaluronic-acid as a substitute for proteins in the deep-freezing of embryos from mice and sheep – an in vitro investi- Luo Y, Ziebell MR, Prestwich GD. (2000). A hyaluronic acid-taxol antitumor gation. Theriogenology 37: 473–480. bioconjugate targeted to cancer cells. Biomacromolecules 1: 208–218. Juranek I, Soltes L. (2012). Reactive oxygen species in joint physiology: Possible Maheu E, Ayral X, Dougados M. (2002). A hyaluronan preparation (500– mechanism of maintaining hypoxia to protect chondrocytes from oxygen ex- 730 kDa) in the treatment of osteoarthritis: a review of clinical trials with cess via synovial fl uid hyaluronan peroxidation. In: “Kinetics, Catalysis and Hyalgan(R). Int J Clin Pract 56: 804–813. Mechanism of Chemical Reactions: From Pure to Applied Science. Volume Manuskiatti W, Maibach HI. (1996). Hyaluronic acid and skin: wound healing 2 – Tomorrow and Perspectives” R.M. Islamova, S.V. Kolesov, G.E. Zaikov and aging. Int J Dermatol 35: 539–544. (eds), Nova Science Publishers, New York pp. 1–10 Mazzucco D, Scott R, Spector M. (2004). Composition of joint fl uid in patients Kano K, Miyano T, Kato S. (1998). Eff ects of glycosaminoglycans on the devel- undergoing total knee replacement and revision arthroplasty: correlation opment of in vitro matured and fertilized porcine oocytes to the blastocyst with fl ow properties. Biomaterials 25: 4433–4445. stage in vitro. Biol Reprod 58: 1226–1232. McCord JM. (1974). Free radicals and infl ammation: protection of synovial Kelly MA, Goldberg VM, Healy WL. (2003). Osteoarthritis and beyond: a con- fl uid by superoxide dismutase. Science 185: 529–531. sensus on the past, present, and future of hyaluronans in orthopedics. Or- thopedics 26: 1064–1079. McDonald JN, Levick JR. (1988). Morphology of surface synoviocytes in situ at normal and raised joint pressure, studied by scanning electron micros- Kemmann E. (1998). Creutzfeldt-Jakob disease (CJD) and assisted reproduc- copy. Ann Rheum Dis 47: 232–240. tive technology (ART) – quantifi cation of risks as part of informed consent. Hum Reprod 13: 1777. McDonald JN, Leviek JR. (1995). Eff ect of intra-articular hyaluronan on pres- sure-fl ow relation across synovium in anaesthetized rabbits. J Physiol Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, de Souza 485(Pt.1): 179 –93. Wyse AT, Wannmacher CMD. (2008). Antioxidant eff ect of cysteamine in brain cortex of young rats. Neurochem Res 33: 737–44. Mendichi R, Soltes L. (2002). Hyaluronan molecular weight and polydisper- Kim A, Checkla DM, Dehazya P, Chen WL. (2003). Characterization of DNA- sity in some commercial intra-articular injectable preparations and in sy- novial fl uid In amm fl Res 51: 115–116. hyaluronan matrix for sustained gene transfer. J Control Release 90: 81–95. Kirwan J. (2001). Is there a place for intra-articular hyaluronate in osteoarthri- Meyer K, Palmer JW. (1934). The polysaccharide of the vitreous humor. Jour- tis of the knee? Knee 8: 93–101. nal of Biology and Chemistry 107: 629–634. ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Miltner O, Schneider U, Siebert CH. (2002). Effi cacy of intraarticular hyal- Prisell PT, Camber O, Hiselius J, Norstedt G. (1992). Evaluation of hyaluronan uronic acid in patients with osteoarthritis–a prospective clinical trial. Os- as a vehicle for peptide growth factors. Int J Pharm 85: 51–56. teoarthritis Cartilage 10: 680–686. Radin EL, Swann DA, Weisser PA. (1970). Separation of a hyaluronate-frec lu- Miyano T, Hirooka RE, Kano K. (1994). Eff ects of hyaluronic-acid on the de- bricating fraction from synovial fl uid. Nature 228: 377–8. velopment of 1-cell and 2-cell porcine embryos to the blastocyst stage in- Rapta P, Valachova K, Gemeiner P, Soltes L. (2009). High-molar-mass hyaluro- vitro. Theriogenology 41: 1299–1305. nan behavior during testing its radical scavenging capacity in organic and aqueous media: Eff ects of the presence of Manganese (II) ions. Chem Bio- Miyazaki M, Sato S, Yamaguchi T. (1983). Analgesic and antiin ammat fl ory ac- tion of hyaluronic sodium, Japan Pharmacological Conference. Tokyo, April divers 6: 162–169. 4, 1983. Rapta P, Valachová K, Gemeiner P, Šoltés L. (2009). High-molar-mass hyaluro- Miyazaki T, Miyauchi S, Nakamura T. (1996). The eff ect of sodium hyaluronate nan behavior during testing its antioxidant properties in organic and aque- on the growth of rabbit cornea epithelial cells in vitro. J Ocul Pharmacol ous media: eff ects of the presence of Mn(II) ions. Chem Biodivers 6: 162–169. Ther 12: 409–415. Rapta P, Valachová K, Zalibera M, Šnirc V, Šoltés L. (2010). Hyaluronan degrada- Momberger TS, Levick JR, Mason RM. (2005). Hyaluronan secretion by syn- tion by reactive ox ygen species: scavenging eggect of the hexapyridoindole sto- badine and two of its derivatives. In Monomers, Oligomers, Polymers, Com- oviocytes is mechanosensitive. Matrix Biol 24: 510–519. posites, and Nanocomposites, Ed: R. A. Pethrick P. Petkov, A. Zlatarov G. E. Moreira CA, Armstrong DK, Jelliff e RW. (1991). Sodium hyaluronate as a car- Zaikov, S. K. Rakovsky, Nova Science Publishers, N.Y, Chapter 7, pp. 113–126. rier for intravitreal gentamicin – an experimental study. Acta Ophthalmol (Copenh) 69: 45–49. Rees MD, Kennett EC, Whitelock JM, Davies MJ. (2008). Oxidative damage to extracellular matrix and its role in human pathologies. Free Radical Biol. Moreira CA, Moreira AT, Armstrong DK. (1991). In vitro and in vivo studies with Med 44: 1973–2001. sodium hyaluronate as a carrier for intraocular gentamicin. Acta Ophthal- Revell PA. (1989). Synovial lining cells. Rheumatol Int 9: 49–51. mol (Copenh) 69: 50–56. Morimoto K, Metsugi K, Katsumata H. (2001). Eff ects of lowviscosity sodium Risberg B. (1997). Adhesions: preventive strategies. Eur J Surg 163: 32–39. hyaluronate preparation on the pulmonary absorption of rh-insulin in rats. Rittig M, Tittor F, Lutjen-Drecoll E, Mollenhauer J, Rauterberg J. (1992). Immu- Drug Dev Ind Pharm 27: 365–371. nohistochemical study of extracellular material in the aged human syno- vial membrane. Mech Ageing Dev 64: 219–234. Morimoto K, Yamaguchi H, Iwakura Y. (1991). Eff ects of viscous hyaluronate- sodium solutions on the nasal absorption of vasopressin and an analog. Rychly J, Soltes L, Stankovska M, Janigova I, Csomorova K, Sasinkova V, Kogan Pharmacol Res 8: 471–474. G, Gemeiner P. (2006). Unexplored capabilities of chemiluminescence and thermoanalytical methods in characterization of intact and degraded hyal- Morris ER, Rees DA, Welsh EJ. (1980). Conformation and dynamic interactions uronans. Polym Degrad Stab 91(12): 3174–3184. in hyaluronate solutions. J Mol Biol 138: 383–400. Saettone MF, Giannaccini B, Chetoni P, et al. (1991). Evaluation of highmolec- Myint P. (1987). The reactivity of various free radicals with hyaluronic acid ular-weight and low-molecular-weight fractions of sodium hyaluronate steady-state and pulse radiolysis studies. Biochim Biophys-Aeta 925: 194 –202. and an ionic complex as adjuvants for topical ophthalmic vehicles contain- Necas J, Bartosikova L, Brauner P, Kolar J. (2008). Hyaluronic acid (hyaluro- ing pilocarpine. Int J Pharm 72: 131–139. nan): a review. Veterinarni Medicina 53(8): 397–411. Saettone MF, Monti D, Torracca MT, Chetoni P. (1994). Mucoadhesive oph- Niwa Y, Sakane T, Shingu M, Yokoyama MM. (1983). Eff ect of stimulated neu- thalmic vehicles – evaluation polymeric low-viscosity formulations. J Ocul trophils from the synovial fl uid of patients with rheumatoid arthritis on Pharmacol 10: 83–92. lymphocytes: a possible role of increased oxygen radicals generated by Sakurai K, Miyazaki K, Kodera Y. (1997). Anti-infl ammatory activity of superox- the neutrophils. J Clin Immunol 3: 228–240. ide dismutase conjugated with sodium hyaluronate. Glycoconj J 14: 723–728. Noble PW. (2002). Hyaluronan and its catabolic products in tissue injury and Sasaki H, Yamamura K, Nishida K. (1996). Delivery of drugs to the eye by topi- repair. Matrix Biol 21: 25–29. cal application. Prog Retinal Eye Res 15: 583–620. Oates KMN, Krause WE, Colby RH. (2002). Using rheology to probe the mech- Sattar A, Kumar S, West DC. (1992). Does hyaluronan have a role in endothe- anism of joint lubrication: polyelectrolyte/protein interactions in synovial lial cell proliferation ofthe synovium. Semin. Arthritis Rheum 22: 37–43. fl uid. Mat Res Soc Syrnp Proc 711: 53–58. Schartz RA. (1997). The actinic keratoses. A perspective and update. Dermatol Ogston AG, Stanier JE. (1953). The physiological function of hyaluronic acid in Surg 23: 1009–1019. synovial fl uid viscous, elastic and lubricant properties. J Physiol 199: 244– Schiller J, Volpi N, Hrabarova E, Soltes L. (2011). Hyaluronic acid: a natural bio- polymer In: “Handbook of Biopolymers and Their Applications” S. Kalia and Ortonne JP. (1996). A controlled study of the activity of hyaluronic acid in the L. Averous (eds), Wiley & Scrivener Publishing, USA pp. 3–34. treatment of venous leg ulcers. J Dermatol Treatment 7: 75–81. Schmid T, Lindley K, Su J, Soloveychik V, Block J, Kuettner K, Schumacher B. Orvisky E, Soltes L, Chabrecek P, Novak I, Kery V, Stancikova M, Vins I. (1992). (2001a). Superfi cial zone protein (SZP) is an abundant glycoprotein in hu- The determination of hyaluronan molecular weight distribution by means man synovial fl uid and serum. Trans Orthop Res Soc 26: 82. of high perfeormance size exclusion chromatography. J Liq Chromatogr 15: 3203–3218. Schmid T, Soloveychik V, Kuettner K, Schumacher B. (2001b). Superfi cial zone protein (SZP) from human cartilage has lubrication activity. Trans Orthop Parsons BJ, Al-Assaf S, Navaratnam S, Phillips GO. (2002). Comparison of the Res Soc 26: 178. reactivity of diff erent oxidative species (ROS) towards hyaluronan, in: Kennedy JF, Phillips GO, Williams PA, Hascall VC (Eds.), Hyaluronan: Chemical, Bio- Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. (1994). A chemical and Biological Aspects, Woodhead, Publishing Ltd, Cambridge, novel proteoglycan synthesized and secreted by chondrocytes of the su- MA, pp. 141–150. perfi cial zone of articular cartilage. Arch Biochem Biophys 311: 144–152. Peer D, Florentin A, Margalit R. (2003). Hyaluronan is a key component in Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. (1999). cryoprotection and formulation of targeted unilamellar liposomes. Bio- Immunodetection and partial c DNA sequence of the proteoglycan, super- chim Biophys Acta-Biomembranes 1612: 76–82. fi cial zone protein, synthesized by cells lining synovial joints. J Orthop Res 17: 110–120. Peer D, Margalit R. (2000). Physicochemical evaluation of a stability-driven approach to drug entrapment in regular and in surface-modifi ed lipo- Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL. (2005). Proteo- somes. Arch Biochem Biophys 383: 185–190. glycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J Orthop Res 23: 562–568. Poli A, Mason RM, Levick JR. (2004). Eff ects of Arg- Gly-Asp sequence peptide and hyperosmolarity on the permeability of interstitial matrix and fenes- Schwarz IM, Hills BA. (1996). Synovial surfactant: lamellar bodies in type B trated endothelium in joints. Microcirculation 11: 463–476. synoviocytes and proteolipid in synovial fl uid and the articular lining. Br J Rheumatol 35: 821–827. Praest BM, Greiling H, Kock R. (1997). Eff ects of oxygen-derived free radicals on the molecular weight and the polydispersity of hyaluronan solutions. Schwarz IM, Hills BA. (1998). Surface-active phospholipids as the lubricating Carbohydr Res 303 :153–157 . component of lubricin. Br J Rheumatol 37: 21–26. Price FM, Levick JR, Mason RM. (1996). Glycosaminoglycan concentration in Scott DL, Shipley M, Dawson A, Edwards S, Symmons DP, Woolf AD. (1998). synovium and other tissues of rabbit knee in relation to synovial hydraulic The clinical management of rheumatoid arthritis and osteoarthritis: strate- resistance. J Physiol (Lond) 495: 803–820. gies for improving clinical eff ectiveness. Br J Rheumatol 37: 546–554. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc. Hyaluronan and synovial joint Tamer Mahmoud Tamer Scott JE, Cummings C, Brass A, Chen Y. (1991). Secondary and tertiary struc- Surini S, Akiyama H, Morishita M. (2003). Polyion complex of chitosan and so- tures of hyaluronan in aqueous solution, investigated by rotary shadowing- dium hyaluronate as an implant device for insulin delivery. STP Pharm Sci electron microscopy and computer simulation. Biochem J 274: 600–705. 13: 265–268. Servaty R, Schiller J, Binder H, Arnold K. (2000). Hydration of polymeric com- Surovcikova L, Valachova K , Banasova M, Snirc V, Priesolova E, Nagy M, Juranek ponents of the cartilage – An infrared spectroscopic study on hyaluronic I, Soltes L. (2012). Free-radical degradation of high-molar-mass hyaluronan acid and chondroitin sulfate. Int J Biol Macromol 28: 123–129. induced by ascorbate plus cupric ions: Testing of stobadine and its two derivatives in function as antioxidants. General Physiol Biophys 31: 57–64. Simkovic I, Hricovini M, Soltes L, Mendichi R, Cosentino C. (2000). Preparation of water soluble/insoluble derivatives of Hyaluronic acid by cross linking Swann DA, Silver FH, Slayter HS, Staff ord W, Shore E. (1985). The molecular with epichlorohydrin in aqueous NaOH/NH OH solution. Carbohydr Polym structure and lubricating activity of lubricin isolated from bovine and hu- 41: 9–14. man synovial fl uids. Biochem J 225: 195–201. Simon A, Safran A, Revel A. (2003). Hyaluronic acid can successfully replace Takayama K, Hirata M, Machida Y. (1990). Eff ect of interpolymer complex-for- albumin as the sole macromolecule in a human embryo transfer medium. mation on bioadhesive property and drug release phenomenon of com- Fertil Steril 79: 1434–1438. pressed tablet consisting of chitosan and sodium hyaluronate. Chem Phar- maceut Bull 38: 1993–1997. Soldati D, Rahm F, Pasche P. (1999). Mucosal wound healing after nasal sur- gery. A controlled clinical trial on the effi cacy of hyaluronic acid containing Tani E, Katakami C, Negi A (2002). Eff ects of various eye drops on corneal cream. Drugs Exp Clin Res 25: 253–261. wound healing after superfi cial keratectomy in rabbits. Jpn J Ophthalmol 46: 488–495. Soloveva ME, Solovev VV, Faskhutdinova AA, Kudryavtsev AA, Akatov VS. (2007). Prooxidant and cytotoxic action of N-acetylcysteine and glutathi- Tascioglu F, Oner C. (2003). Effi cacy of intra-articular sodium hyaluronate in one in combinations with vitamin B12b. Cell Tissue Biol 1: 40–49. the treatment of knee osteoarthritis. Clin Rheumatol 22: 112–117. Soltes L, Kogan G. (2009). Impact of transition metals in the free-radical degra- Thibodeau PA, Kocsis-Bedard S, Courteau J, Niyonsenga T, Paquette B. (2001). dation of hyaluronan biopolymer In: “Kinetics & Thermodynamics for Chem- Thiols can either enhance or suppress DNA damage induction by catecho- istry & Biochemistry: Vol. 2” E. M. Pearce, G. E. Zaikov, G. Kirshenbaum (eds), lestrogens. Free Radic Biol Med 30: 62–73. Nova Science Publishers, New York (181–199). Turino GM, Cantor JO. (2003). Hyaluronan in respiratory injury and repair. Am Soltes L, Mendichi R, Kogan G, Mach M. (2004). Associating Hyaluronan De- J Respir Crit Care Med 167: 1169–1175. rivatives: A Novel Horizon in Viscosupplementation of Osteoarthritic Uthman I, Raynauld JP, Haraoui B. (2003). Intra-articular therapy in osteoar- Joints. Chem Biodivers 1: 468–472. thritis. Postgrad Med J 79: 449–453. Soltes L, Brezova V, Stankovska M, Kogan G, Gemeiner P. (2006a). Degrada- Valachova K, Vargova A, Rapta P, Hrabarova E, Drafi F, Bauerova K, Juranek tion of high-molecular-weight hyaluronan by hydrogen peroxide in the I, Soltes L. (2011). Aurothiomalate as preventive and chain-breaking anti- presence of cupric ions. Carbohydr Res 341: 639–644. oxidant in radical degradation of high-molar-mass hyaluronan. Chemistry Soltes L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. (2006b) & Biodiversity 8: 1274–1283. Degradative action of reactive oxygen species on hyaluronan. Biomacro- Valachova K, Banasova M, Machova L, Juranek I, Bezek S, Soltes L. (2013b). molecules 7: 659–668. Antioxidant activity of various hexahydropyridoindoles. Journal of Informa- Soltes L, Stankovska M, Brezova V, Schiller J, Arnhold J, Kogan G, Gemeiner P. tion Intelligence and Knowledge 5: 15–32. (2006c). Hyaluronan degradation by copper (II) chloride and ascorbate: ro- Valachova K, Hrabarova E, Priesolova E, Nagy M, Banasova M, Juranek I, Soltes tational viscometric, EPR spin-trapping, and MALDI-TOF mass spectromet- L. (2011). Free-radical degradation of high-molecular-weight hyaluronan in- ric investigations Carbohydr Res 341: 2826–2834. duced by ascorbate plus cupric ions. Testing of bucillamine and its SA981- Soltes L, Stankovska M, Kogan G, Germeiner P, Stern R. (2005). Contribution metabolite as antioxidants. J Pharma & Biomedical Analysis 56: 664–670. of oxidative reductive reations to high molecular weight hyaluronan ca- Valachová K, Hrabárová E, Dráfi F, Juránek I, Bauerová K, Priesolová E, Nagy tabolism. Chem Biodivers 2: 1242–1245. M, Šoltés L. (2010a). Ascorbate and Cu(II) induced oxidative degradation of Soltes L, Valachova K, Mendichi R, Kogan G, Arnhold J, Gemeiner P. (2007). high-molar-mass hyaluronan. Pro- and antioxidative eff ects of some thiols. Solution properties of high-molar-mass hyaluronans: the biopolymer deg- Neuroendocrinol Lett 31(2): 101–104. radation by ascorbate. Carbohydr Res 342: 1071–1077. Valachová K, Hrabárová E, Gemeiner P, Šoltés L. (2008). Study of pro- and Soltes L. (2010). Hyaluronan – A High-Molar-Mass Messenger Reporting on the anti-oxidative properties of d-penicillamine in a  system comprising high- Status of Synovial Joints: Part II. Pathophysiological Status In: “New Steps in molar-mass hyaluronan, ascorbate, and cupric ions. Neuroendocrinol Lett Chemical and Biochemical Physics. Pure and Applied Science” E. M. Pearce, 29: 697–701. G. Kirshenbaum, G. E. Zaikov (eds), Nova Science Publishers, New York pp. Valachová K, Hrabárová E, Juránek I, Šoltés L. (2011b). Radical degradation of 137–152. high-molar-mass hyaluronan induced by Weissberger oxidative system. Stankovska M, Arnhold J, Rychly J, Spalteholz H, Gemeiner P, Soltes L. (2007). Testing of thiol compounds in the function of antioxidants. 16th Interdisci- In vitro screening of the action of non-steroidal anti-infl ammatory drugs on plinary Slovak-Czech Toxicological Conference in Prague. Interdiscip Toxicol hypochlorous acid-induced hyaluronan degradation. Polym Degrad Stabil 4(2): 65. 92: 644–652. Valachová K, Kogan G, Gemeiner P, Šoltés L. (2008b). Hyaluronan degrada- Stankovska M, Soltes L, Vikar tovska A, Mendichi r, Lath D, Molnarova M, Gemei- tion by ascorbate: Protective eff ects of manganese (II). Cellulose Chem. ner P. (2004). Study of hyaluronan degradation by means of rotational Vis- Technol 42(9–10): 473−483. cometry: Contribution of the material of viscometer. Chem Pap 58: 348–352. Valachová K, Kogan G, Gemeiner P, Šoltés L. (2009b). Hyaluronan degrada- Stankovska M, Hrabarova E, Valachova K, Molnarova M, Gemeiner P, Soltes L. tion by ascorbate: protective eff ects of manganese (II) chloride. In: Progress in (2006). The degradative action of peroxynitrite on high-molecular-weight Chemistry and Biochemistry. Kinetics, Thermodynamics, Synthesis, Proper- hyaluronan . Neuroendocrinol Lett 27(Suppl. 2): 31–34. ties and Application, Nova Science Publishers, N.Y, Chapter 20, pp. 201–215. Stankovska M, Soltes L, Vikartovska A, Gemeiner P, Kogan G, Bakos D. (2005). Valachová K, Mendichi R, Šoltés L. (2010c). Eff ect of L-glutathione on high-mo- Degradation of high-molecular-weight hyaluronan: a rotational viscome- lar-mass hyaluronan degradation by oxidative system Cu(II) plus ascorbate. In: try study. Biologia 60(Suppl. 17): 149–152. Monomers, Oligomers, Polymers, Composites, and Nanocomposites, Ed: R. Stern R, Kogan G, Jedrzejas M. J, Soltes L. (2007). The many ways to cleave hy- A. Pethrick P. Petkov, A. Zlatarov G. E. Zaikov, S. K. Rakovsky, Nova Science aluronan. Biotechnol Adv 25: 537–557. Publishers, N.Y, Chapter 6, pp. 101–111. Stiebel-Kalish H, Gaton DD, Weinberger D. (1998). A comparison of the eff ect Valachová K, Rapta P, Kogan G, Hrabárová E, Gemeiner P, Šoltés L. (2009a). of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye 12: Degradation of high-molar-mass hyaluronan by ascorbate plus cupric ions: 829–833. eff ects of D-penicillamine addition. Chem Biodivers 6: 389–395. Suchanek E, Simunic V, Juretic D, Grizelj V. (1994). Follicular-fl uid contents of Valachová K, Rapta P, Slováková M, Priesolová E, Nagy M, Mislovičová D, Dráfi hyaluronic-acid, follicle-stimulating-hormone and steroids relative to the F, Bauerová K, Šoltés L. (2013a). Radical degradation of high-molar-mass hy- success of in-vitro fertilization of human oocytes. Fertil Steril 62: 347–352. aluronan induced by ascorbate plus cupric ions. Testing of arbutin in the func- Surendrakumar K, Martyn GP, Hodgers ECM. (2003). Sustained release of in- tion of antioxidant. In: Advances in Kinetics and Mechanism of Chemical Re- sulin from sodium hyaluronate based dry powder formulations after pul- actions, G. E. Zaikov, A. J. M. Valente, A. L. Iordanskii (eds), Apple Academic monary delivery to beagle dogs. J Control Release 91: 385–394. Press, Waretown, NJ, USA, pp. 1–19.  ISSN: 1337-6853 (print version) | 1337-9569 (electronic version) Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125 Also available online on PubMed Central Valachová K, Šoltés L. (2010b). Eff ects of biogenic transition metal ions Zn(II) Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. (1992). Light microscopic characterization of the fi broblastlike synovial intimal cell (synoviocyte). Ar- and Mn(II) on hyaluronan degradation by action of ascorbate plus Cu(II) ions. thritis Rheum 35: 1179–1184. In: New Steps in Chemical and Biochemical Physics. Pure and Applied Sci- ence, Nova Science Publishers, Ed: E. M. Pearce, G. Kirshenbaum, G.E. Zai- Worrall JG, Bayliss MT, Edwards JC. (1991). Morphological localization of hyal- uronan in normal and diseased synovium. J Rheumatol 18: 1466–1472. kov, Nova Science Publishers, N.Y, Chapter 10, pp. 153–160. Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC. (1994). Zonal distribution of Valachová K, Vargová A, Rapta P, Hrabárová E, Dráfi F, Bauerová K, Juránek chondroitin-4-sulphate/ dermatan sulphate and chondroitin-6-sulphate in I, Šoltés L. (2011a). Aurothiomalate in function of preventive and chain- normal and diseased human synovium. Ann Rheum Dis 53: 35–38. breaking antioxidant at radical degradation of high-molar-mass hyaluro- Yerushalmi N, Arad A, Margalit R. (1994). Molecular and cellular studies of hy- nan. Chem Biodivers 8: 1274–1283. aluronic acid-modifi ed liposomes as bioadhesive carriers for topical drug- Vanos HC, Drogendijk AC, Fetter WPF. (1991). The infl uence of contamination delivery in wound-healing. Arch Biochem Biophys 313: 267–273. of culture-medium with hepatitis-B virus on the outcome of in vitro fertil- Yerushalmi N, Margalit R. (1998). Hyaluronic acid-modifi ed bioadhesive lipo- ization pregnancies. Am J Obstet Gynecol 165: 152–159. somes as local drug depots: eff ects of cellular and fl uid dynamics on lipo- Vazquez JR, Short B, Findlow AH. (2003). Outcomes of hyaluronan therapy in some retention at target sites. Arch Biochem Biophys 349: 21–26. diabetic foot wounds. Diabetes Res Clin Pract 59: 123–127. Yun YH, Goetz DJ, Yellen P, Chen W. (2004). Hyaluronan microspheres for sus- Weigel PH, Hascall VC, Tammi M. (1997). Hyaluronan synthases. J Biol Chem tained gene delivery and site-specifi c targetting. Biomaterials 25: 147–157. 272: 13997–14000. Zhu YX, Granick S. (2003). Biolubrication: hyaluronic acid and the infl uence West DC, Hampson IN, Arnold F, Kumar S. (1985). Angiogenesis induced by on its interfacial viscosity of an antiinfl ammatory drug. Macromolecules 36: 973–976. degradation products of hyaluronic acid. Science 228: 1324–1326. Copyright © 2013 SETOX & Institute of Experimental Pharmacology and Toxicology, SASc.

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