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Hindawi Publishing Corporation Advances in Orthopedic Surgery Volume 2014, Article ID 850594, 23 pages http://dx.doi.org/10.1155/2014/850594 Review Article Ultrastructure of Intervertebral Disc and Vertebra-Disc Junctions Zones as a Link in Etiopathogenesis of Idiopathic Scoliosis 1 1 1 Evalina L. Burger, Andriy Noshchenko, Vikas V. Patel, 1 2 Emily M. Lindley, and Andrew P. Bradford The Spine Center, Department of Orthopaedics, University of Colorado Denver, Aurora, CO 80045, USA Division of Basic Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Denver, Aurora, CO 80045, USA Correspondence should be addressed to Andriy Noshchenko; firstname.lastname@example.org Received 24 September 2013; Accepted 1 February 2014; Published 23 March 2014 Academic Editor: Chan S. Shim Copyright © 2014 Evalina L. Burger et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background Context. er Th e is no general accepted theory on the etiology of idiopathic scoliosis (IS). An important role of the vertebrae endplate physes (VEPh) and intervertebral discs (IVD) in spinal curve progression is acknowledged, but ultrastructural mechanisms are not well understood. Purpose. To analyze the current literature on ultrastructural characteristics of VEPh and IVD in the context of IS etiology. Study Design/Setting. A literature review. Results. er Th e is strong evidence for multifactorial etiology of IS. Early wedging of vertebra bodies is likely due to laterally directed appositional bone growth at the concave side, caused by a combination of increased cell proliferation at the vertebrae endplate and altered mechanical properties of the outer annulus b fi rosus of the adjacent IVD. Genetic defects in bending proteins necessary for IVD lamellar organization underlie altered mechanical properties. Asymmetrical ligaments, muscular stretch, and spine instability may also play roles in curve formation. Conclusions. Development of a reliable, cost eeff ctive method for identifying patients at high risk for curve progression is needed and could lead to a paradigm shift in treatment options. Unnecessary anxiety, bracing, and radiation could potentially be minimized and high risk patient could receive surgery earlier, rendering better outcomes with fewer fused segments needed to mitigate curve progression. 1. Introduction slow deformation of the vertebrae through remodeling with disc herniation and neural compression. Hence in adult There is no generally accepted scientific theory for the scoliosis a stable balance is necessary to prevent further etiology of idiopathic scoliosis (IS). Treatment of this disease deformation of the spine [3–5]. remains pragmatic with an incomplete scientific basis [ 1]. The IS maybeobservedinthe infantile, juvenile,orado- lescent period, but the trigger factor for curve onset is current strategy of treatment depends on a patient’s age . In children, scoliotic deformity causes a persistent stress in the unknown. eTh re is evidence that the spinal growth spurt motion segments, which induces a progressive elastoplastic plays a significant role in the onset and progression of spinal deformation, especially in the adolescent period. It has been strain that modifies the geometry of the motion segment, which in turn worsens the excessive strain [2, 3]. u Th s, in the shownthatspinalgrowthcan be attributed to increasesinthe pediatric spine the aim of treatment is to prevent the motion vertebrae height, while the height of discs does not increase segment deformity. In adult scoliosis, significant deformation [1, 6]. Thisislikelymodulated by loading, accordingtothe of the intervertebral disc (IVD) and the capsuloligamentous Hueter-Volkmann principle [2, 7]. Human vertebrae grow structures produce instability of the motion segments and longitudinally by ossification of the vertebral endplate physes 2 Advances in Orthopedic Surgery (VEPh). VEPh adjacent to the discs produce longitudinal seldom present at birth and mainly develops during the first growth, while appositional growth enlarges the vertebrae in 6 month of life. Resolved curves typically do not recur during diameter [1, 8]. Theoretically, axial compression can diminish the adolescent growth spurt. In adulthood very few patients axial growth by reducing the number of proliferating chon- have back pain or an increased disability score [13, 17, 18]. drocytes in the hypertrophic zone . Wedging of discs in Thoracic and lumbar curves that reach between 50 and 80 scoliosis may be caused by asymmetric tissue remodeling or degrees at skeletal maturity may continue to progress slowly selective concave side degeneration . As scoliosis tends in adult life . IIS is also associated with plagiocephaly to progress during the growth spurt, it is possible that the (100% of children with early onset of IIS), mental retardation, growth plate plays an important role in the development congenital heart disease, and congenital dislocation of the hip of the deformity [9–11]. The interaction between VEPh and . Congenital inguinal hernia and generalized joint laxity adjoined IVD could play a significant role in the initiation and have been found among relatives of diseased children . progression of the spinal deformation, especially at the apical Using magnetic resonance imaging (MRI) demonstrated that zone. Stokes and Aronsson noted that whilethe IVD the incidence of neural axis abnormalities in children with IIS does not appear to be the primary factor in the etiology of IS, and JIS is around 20% including Arnold-Chiari malforma- the IVD contributes to the progression of the scoliosis curve tion, associated cervicothoracic syringx, syringomyelia, and when it becomes significantly wedged. The IVD interface low-lying conus [21, 22]. Wynne Davies suggested that under load shows characteristics of dysplasia which can be the etiology of IIS must be multifactorial, with a genetic associated with changes in discal properties . Despite many tendency to the deformity which can then be “triggered off” studies on the etiology and pathogenesis of scoliosis, the in different individuals by different factors, some medical, interaction between VEPh and IVD both morphologically some themselves genetic, and some social. JIS is prevalent and ultrastructurally has not been studied well. in boys between ages four and six and in girls between ages The purpose of the present paper is to review current seven and nine [13, 23, 24]. Right sided curves are observed literature on the morphological and ultrastructural charac- in 50–77.5% of cases, regardless of sex or age. A single teristics of the IVD and the VEPh in relation to the clinical thoracic curve is the most common (around 62%), followed manifestation of IS, with an emphasis on the etiology and by double thoracic and lumbar (22%) and thoracolumbar pathogenesis of this disease. We below present a review of: (15%). Curve progression is difficult to predict. Spontaneous (a) clinical manifestation of IS; (b) etiological and patho- resolutions are much less common than in IIS (around genetic factors and concepts of IS; (c) morphological and 7%) , and progression may occur in more than 50% ultrastructural features of the IVD and VEPh in IS. eTh of cases . Associated diseases were observed in 29% following sources of information were used to collect the of patients including mental deficiency (12%), spina bifida data: (1) electronic data bases: Ovid Medline and Embase occulta (6%), inguinal hernia (3%), epilepsy (2%), pyloric till September 2013; (2) hand search using reference lists of stenosis (2%), congenital dislocation of hip (1%), dextrocardia reviews and book chapters; no restrictions concerning type (1%), metatarsus varus (1%), joint laxity (1%), hemimelia (1%), of publication and language were used. and absent thumb (1%) . Around 13% of all patients with JIShaveahistoryoffamilyinvolvement . Patients with JIS are at risk of curve progression during pubertal growth, especially if the curve exceeds 30 at the onset of the pubertal 2. Clinical Manifestation of IS growth spurt . AIS occurs in 2–4% of children during the pubertal growth spurt, mainly in females [14, 26, 27]. IS was originally defined as a structural, lateral curvature of the spine of unknown etiology . The Scoliosis Research The ratio of girls to boys increases from 1.6 : 1 at 9-10 years Society then defined scoliosis as a lateral curvature of the of age to 6.4 : 1 at 11-12 years of age . Thoracic curves spine which exceeds 10 degrees by the Cobb method on a areobservedin33%–48% [28–30], thoracolumbar/lumbar standing radiograph . Later it was noted that the presence 21%–40% [28–30], double/triple curves 9%–38% [28–30], of structural rotation at the apical segment is essential and lumbar curves around 8% [28, 29]. Data concerning . Currently, scoliosis is regarded as a three-dimensional rate of curve progression are heterogeneous and vary from curvature of the spine in the coronal and sagittal planes with 1.6% to 68% depending on the study and subjects enrolled . Soucacos et al.  reported by results of 6-year rotation in the axial plane . If the curvature is present before skeletal maturity and has no other diagnostic features prospective cohort study in Greek population that curve that categorize it as neuromuscular, congenital, traumatic, progression occurs in around 15% of children with AIS, while 27.4% demonstrate spontaneous improvement of at infectious, postinfectious, or syndrome-related, then it is regarded as IS . The age of onset is the basis of the least 5 degrees. Xu et al. suggested that in skeletally classification. Infantile IS (IIS) idiopathic scoliosis (IIS) starts immature AIS patients (Risser sign 0–3) with initial curve before age 3 (≈1% of cases), juvenile (JIS) occurs between magnitude ranging from 20 to 40 degrees rate of curve 3 and 10 years (around 20% of cases), while adolescent IS progression was 24%–32% depending on the type of spine deformity. Risk factors for curve progression include type (AIS) is defined, if curve onset is between 10 years and skeletal maturity . There are also distinctions in the of spine deformity, in particular, right thoracic and double clinical appearance between different forms of IS. IIS oen ft curves in girls, and right lumbar curves in boys; age at onset of menses in girls (although data are contradictive); has spontaneous resolutions (20% and 80%), predominant in boys, and mostly has left thoracic curvature. The curve is menarche status; skeletal maturity (Risser sign 0–3); and Advances in Orthopedic Surgery 3 curve magnitude equal to or greater than 30 [32, 33]. An The results of the experimental and clinical studies all MRIstudy of thebrainstem andspinalcordshowedthat confirm the association of the CNS disorders with scoliosis 2% of children with presumed AIS had such abnormalities development [38–46]. Unfortunately it is dicffi ult to conclude as hydrosyringomyelia, Arnold-Chiari malformation teth- whether the CNS dysfunctions reflect a possible cause of ered spinal cord, tumor, and diastematomyelia . This is scoliotic spine deformity, consequence, or whether they approximately ten times less than in patients with infan- develop parallel to the curve formation. tile and juvenile IS. An epidemiological case-control study According to the Neurodevelopmental concept, which revealed evidence of a genetic component in the etiology of regards dysfunction of the CNS as a primary factor of IS, AIS . changes in the vertebrae-disc interaction must be secondary eTh data above imply that genetic predisposition plays and may be caused by the axial load asymmetry. a significant role in the etiology of IS; however genetic determinants of the disease are likely multifactorial. These 3.3. eTh Braking of Bilateral Symmetry in relation to Left-Right variations may determine clinical features such as age of Asymmetry Initiated in Embryonic Life. It has been suggested clinical manifestation, gender, association with congenital that developmental instability may be the initial factor in malformations, type of scoliotic curve, severity of curve scoliotic curve formations having genetic determinants [47– progression, or resolution. 49]. This conclusion was based on the fact that children with AIS have increased left-right asymmetry including arm and leg length, trunk shape, breast size, skull and face, teeth, brain 3. Etiological and Pathogenetic Factors and stem, femoral neck-shaft angles, dermatoglyphic character- Concepts of IS istics, vibration sensitivity, and somatosensory perception [44, 47, 50–56]. Current etiologic research on IS focuses on biological and If the concepts of braking of bilateral symmetry and biomechanical factors and relates mainly to the growth of developmental instability are true, we can expect existence the central nervous system (CNS), disturbances of bilateral of a primordial morphological asymmetry in the structure of symmetry and development instability, hormonal regulation thevertebrae endplates, annulusfibrosus of thediscs, andthe and intercellular signaling, platelet calmodulin, melatonin, disc-vertebrae joints not only at the apical level, but also at muscles, bone density, elastic fibers, and the skeletal frame- other spine levels. work including vertebral disproportionate growth and genet- ics . There are several hypotheses pointing to congenital disorders of the CNS as an important factor in scoliotic spine 3.4. The Neuroendocrine Hypothesis. Initially this hypoth- esis suggested melatonin deficiency as a source for AIS, deformation. eTh following sections describe the primary and stems from the fact that pinealectomized chickens hypotheses. and pinealectomized rats maintained in a bipedal mode developed spine deformities more oen ft than controls [ 57– 3.1. eTh Nottingham Concept. This concept was proposed by 59]. The same result was obtained in melatonin-deficient Burwell and coauthors in 1992 and focuses on the relationship mice without pinealectomy . The spine deformity devel- between developmental abnormality in the CNS and rib- opment in pinealectomized chickens correlated with delay vertebra angle asymmetry, which leads to a cyclical failure of the cortical somatosensory evoked potentials, suggesting of the mechanisms of rotational trunk control involving falls. a conduction disturbance of brain stem function. It was This in turns leads to the initiation of the deformity with loss suggested that these findings implicate neurotransmitters of lordosis. Curve progression occurs as a result of gravity or neurohormonal systems in the pineal body as a major acting on both the abnormal as well as the normal vertebral contributing factor in this type of experimental scoliosis . growth . Machida et al.  reported that the level of serum melatonin was significantly lower in patients who had progressive curves in comparison with those who had a stable curve. eTh level of 3.2. Neurodevelopmental Concept of Maturational Delay of the melatoninappearedtobeausefulpredictorforprogressionof CNS Body Schema. This concept was proposed in 2006 [ 37] spine curvature in IS, but further experiments in nonhuman as a further development of the Nottingham concept and primates and other clinical trials have not confirmed this suggests that spine deformity in scoliosis is the result of a conclusion [62–67]. combination of different factors including left-right skeletal length asymmetries involving growth plates (physes) and probably vertebral body growth plates; periapical rib length 3.5. Impairment of Melatonin Signaling Transduction. Mor- asymmetry; neuromuscular asymmetry; the rapid spinal eau et al.  have shown that melatonin signaling was elongation in the adolescent growth spurt that results from impaired in cultured osteoblasts from AIS patients to differ- growth principally of vertebral body growth plates under the ent degrees allowing their classification in 3 distinct groups. influence of steroid hormones; a delay in CNS maturation The authors suggested the presence of distinct mutations, leading to impaired neuromuscular adjustments on a rapidly interfering with melatonin signal transduction. eir Th conclu- elongating spine; and movement of the spine and trunk in sion was that changes in G-proteins functioning which are the upright posture unique to humans which leads to the an important link in the intracellular melatonin signaling can neuromuscular adjustment of the rapidly elongating spine. be considered a possible mechanism in the etiopathogenesis 4 Advances in Orthopedic Surgery of AIS. A hypofunctionality of G-proteins may be caused by in patients with AIS the longitudinal growth of the spinal increased serine phosphorylation leading to their inactiva- cord fails to keep up with the pace of the growth of the vertebral column (disproportionate neuroosseous growth) tion, which is provided by kinases and phosphatases. Protein . kinase C delta (PKC𝛿 ) is one of them. Azeddine et al.  Basedonthese resultsitispossibletospeculate on the demonstrated the ability of PKC𝛿 to compose a complex with features that we may n fi d in the morphological structure of melatonin receptors MT2 in osteoblast cells derived from AIS vertebrae endplates, intervertebral discs, and their junctions patients. Such complexes were not detected in control cells. in patients with IS. In particular, we may expect to nd fi Further studies have shown an asymmetric expression of increased proliferative activity different from the age related melatonin receptor mRNA in bilateral paravertebral muscles changes and effects of the axial load asymmetry. in patients with AIS . It has been also found that a polymorphism of the promoter of the melatonin receptor 1B (MTNR1B/MT2) gene is associated with AIS . Such 3.6. Platelet Calmodulin as Predictor of Scoliotic Curve Sever- an association was not found for the melatonin receptor 1A ity. The role of platelets in the pathogenesis of IS has been discussed for many years. It was noted that platelets and (MT1) gene . eTh re is also evidence that the function of muscle fibers share the same contractile proteins (actin and G-protein-coupled receptors may be modulated by estrogen. myosin). In scoliotic patients, both spinal and peripheral In particular, 17 beta estradiol may activate MT1 receptors, muscles showed frequent abnormalities when examined by increase MT2 receptors density , and correct or diminish light and electron microscopy [89, 90]. Patients with IS melatoninsignalingdysfunctionrevealedinosteoblaststaken differed from patients with other types of scoliosis [ 89]. from patients with AIS . They had increased calcium content and decreased muscle Melatonin signaling affects cell processes on several levels spindles in their muscles. It was suggested that there is by binding to two specific G-protein coupled receptors, a specific neuromuscular disorder causing IS linked with MT1 and MT2. One or both of these receptors exist on a membrane defect—namely impaired calcium pump . a variety of cell types. Melatonin receptors are associated Structural and functional abnormalities of platelets attributed primarily with four G-protein subunits. Melatonin signaling to a defect of calcium transport in the membrane and/or is generally a negative regulator of cell function via reduction 2+ contractile protein metabolism were also reported in patients of intracellular messengers such as cAMP, Ca ,and cGMP with AIS . Later Kindsfater et al. and Lowe et al. (cyclic guanosine monophosphate) via G-protein subunits.  showed that platelet calmodulin levels correlate with Melatonin also regulates cell processes via nuclear signaling scoliotic curve progression. eTh y even proposed to use this and transcription factors . Melatonin may increase cAMP index as a predictor of the curve progression. The significant accumulation in the osteoblasts of patients with IS . To difficulty in this field was the lack of normal data and the note, cAMP is used for intracellular signaling transduction large variability in baseline levels for platelet calmodulin . and is involved in the regulation of different cell functions, It was suggested that changes in the platelet calmodulin are including synthesis and proliferative activity. er Th e are some acquired and parallel to curve progression reflecting systemic data that cAMP and G-proteins participate in the eeff cts defects of cell membranes . of mechanotransduction in different tissues, including bone and cartilage [76–79]. Changes in the melatonin transduction pathways may significantly modify cellular activity including 3.7. Platelet/Skeletal Hypothesis. Burwell and Dangerefi ld osteoblasts and osteoclasts. Melatonin is an important reg-  proposed the platelet/skeletal hypothesis, which involves ulator of bone modeling and remodeling and is synthesized morphological, mechanical, vascular, platelet, hormonal, and by the pineal gland and bone marrow . Data on the growth mechanisms. This hypothesis assumes that presence direct effect of melatonin on bone cells are contradictory. of a small scoliosis curve in the human upright position It was reported that melatonin promotes osteoblast cell alters the vertebral body growth endplate physes, which differentiation and proliferation [ 81]and increasesbone lead to microinsults. es Th e microinsults activate endothelial mass by suppression resorption through downregulation of cells, which then results in dilated vessels and vascular osteoclast formation and activation . However, other “lakes” adjacent to the disc growth plates. Activated platelets authors report on the suppressive effect of melatonin on circulate through vessels, particularly in the curve apex on osteoblastic and osteoclastic activities . It was noted that the medullary aspect of endplate physes. eTh platelets are an inhibitory effect of melatonin on osteoblastic cells was activated by the slowing of blood flow in the dilated vessels seen when incubated in the presence of osteoclastic cells and vascular “lakes”, repeated mechanical microinsults that . If the inhibitory effect of melatonin on both the cell lead to vascular damage with exposure of endothelial col- linesistrue, we maysuppose that adefectinmelatonin lagen, endothelial cells, and release of different intracellular transduction in combination with other factors contributes signaling factors. Platelet activation is associated with a to the accelerated anterior vertebral endochondral bone calcium-calmodulin complex formation. Vertebrae growth overgrowth, which in turn correlates with scoliotic curve plates are stimulated by growth factors from platelets as occurrence and more active longitudinal growth of patients well as mechanically. It promotes an overgrowth and a with AIS in comparison with their peers [85–87]. Increased spine deformity progression. A molecular predisposition to osteoclast activity may cause stimulation of bone remodeling platelet activation may involve hormones and genetic poly- leading to spine slenderness. It may also explain the fact that morphisms. Advances in Orthopedic Surgery 5 We wouldliketopoint outanother possible mechanism, complex and to incorporate into the extracellular matrix. which may explain the increase of platelet calmodulin levels It wasassumedthatmutations in thegeneencodingfor in some patients with IS. As described above, a defect in mela- fibrillin caused the production of abnormal b fi rillin, such as tonin signaling transduction associated with the impaired of in Marfan’s syndrome. Research in this eld fi is very important G-protein cAMP inhibition was revealed in the osteoblasts not only because ligaments play a significant role in spine of patients with IS . This ndin fi g is consistent with the stability, but also because fibrillins take part in embryonic polymorphism of the promoter of melatonin receptor 1B development, in particular, skeletal elements, and skeletal gene, which was later reported . It should be noted that muscle [105, 106]. In addition, some cells in the annulus human platelets use the same melatonin signaling mecha- fibrosus of IVD have been described as fibroblast-like [ 107]. nisms as in the osteoblasts, including melatonin receptors There is evidence that melatonin may significantly modify the and G-protein-cAMP inhibition system . Besides, mela- activity of fibroblasts. For instance, strong expression of basic tonin inhibits several physiological intracellular processes fibroblast growth factor (bFGF) was found in the epineurium 2+ of rats that underwent pinealectomy in comparison with , including the activity of Ca /calmodulin-dependent control and melatonin treated animals . The role of these protein kinase II (CaM-kinase II), and acts as a universal 2+ mechanisms in the etiopathogenesis of IS has not yet been calmodulin antagonist in cells inhibiting Ca influx [ 98]. investigated. If melatonin signaling is impaired in platelets, then platelet activation may be associated with an increase in cAMP 2+ generation, increase in the calmodulin and Ca levels, and 3.9. Changes of the Hormonal Regulation. Clinical observa- inhibition of aggregation. Inhibition of platelet aggregation tions have revealed a tendency for increased thoracolumbar is used as a marker of decreased G-protein activity and spine height and slenderness in children with IS [86–88, 109]. increased cAMP generation . u Th s, if impaired melatonin Skogland and Miller  showed that girls with IS had a signaling is involved in IS, than platelet aggregation must signicfi antly higher response to the growth hormone stimu- be decreased in patients with IS. Unfortunately, the results lation test than controls. Higher growth hormone secretion of clinical studies are contradictory. Se Il Suk et al.  was also found by Ahl et al. among girlswithISinthe tested bleeding time, platelet aggregation, and titer of platelet pubertal stage. Interestingly, the level of serum somatomedin plasminogen activator inhibitors in 52 patients with IS and A (insulin-like growth factor-2) in girls with IS was lower in 49 controls. Statistically significant differences were not than in controls . Some authors report an increased found. However, a more recent study performed by Ho et al. risk of scoliosis progression in patients treated with growth  showed that among 32 patients with IS who underwent hormone [113, 114], while another did not confirm this finding preoperative coagulation screening tests, 8 had prolonged . Growth hormone (somatotropin) is synthesized and activated partial thromboplastin time and 5 were diagnosed secreted by the anterior pituitary gland. It stimulates growth with a specific coagulation abnormality potentially associated and cell reproduction and stimulates cellular division in car- with increased bleeding. It was concluded that in the tested tilage by acting through both systemic and local insulin-like group of patients with IS, the risk of specific inherited growth factors (IGF) . Several genetic studies have not haemostatic disorders was higher (around 10 times) than in shown a significant association between AIS and the single- the general population. eTh oretically, an increase in platelet nucleotide polymorphism of the growth hormone receptor calmodulin levels and other changes in platelet functions and and IGF-1 gene [117, 118]. However, an association between morphology observed in IS may be a cell specific secondary IGF-1 polymorphism and type of AIS spine deformity was effect of such systemic disorder as melatonin signaling defect, foundinKoreanpopulation. Serum concentration of which is genetically predisposed and linked with melatonin IGF1 significantly correlates with curve acceleration [ 120]. receptors and G-protein dysfunction. It is known that G- It should be noted that melatonin modulates secretion of protein signaling defects in platelets are mainly subclinical growth hormone and IGF in culture, inhibits pituitary cAMP . Also, it has been known for years that certain cellular accumulation, and reduces growth hormone release . functionsofplatelets andinneurosecretorycells arevery Signicfi ant modulation of function of growth hormone func- similar [102, 103]. u Th s, some neurological dysfunctions in IS tion by melatoninwas showninrats. In particular, may also be explained by the melatonin signaling defect. melatonin inhibits endogenous production of IGF1 . u Th s, a defect in melatonin signaling may provoke secondary 3.8. eTh Elastic Fiber System Role in the Pathogenesis of Idio- changes in the function of growth hormone-IGF1 axis and pathic Scoliosis. Hadley-Miller et al. studied theelastic cause bone growth stimulation eect ff s. fiber system using fresh-frozen histological specimens of Published data concerning serum content of testosterone ligamentum flavum removed from 23 patients with scoliosis in AIS are contradictive. Skogland and Miller  revealed and 5 age-matched controls at the time of an operation. significantly increased mean serum levels of testosterone in Abnormalities on immunohistochemical staining including girls with AIS, whose skeletal age was between 9 and 12 years. a marker for disarrangement of the b fi ers and dieff rences Raczkowski alsoreportedonthe relative increased in density of staining were found in 18 of the scoliotic level of testosterone in girls aged 12–17 years with moderate specimens. It was also noted that in 4 scoliotic cases the and severe right thoracic curves (AIS) in comparison with amount of secreted fibrillin was normal, but the fibrillin failed girls of the same age with mild left lumbar scoliosis, while to bind to other macromolecules, to form a sedimentable Esposito et al. revealeddecreaseserum testosterone in 6 Advances in Orthopedic Surgery AIS, but types of spine deformity were not taken into con- IS  require further research and explanation. Current sideration. Theoretically, increased levels of testosterone may experimental data suggest that vitamin D3 and melatonin contribute to vertebrae overgrowth and scoliosis progression. modulate the secretory activity of parathyroid gland [137– Androgens stimulate trabecular and cortical bone modeling 139]. independently from systemic or local IFG1 production in It has been found that blood leptin levels are significantly males . Testosterone metabolism in the growth zone decreased in girls with AIS [140, 141]. It was suggested that chondrocytes of females has some differences causing speci- leptin plays an important role in the lower body mass, ficity of the response [ 127]. Interestingly, nocturnal melatonin growth parameters, and bone mineral density in AIS girls. secretion is increased in patients with hypogonadotropic Causes of the reduced levels of circulating leptin in AIS hypogonadism and testosterone administration normalizes have not been studied yet. Leptin is an adipose derived melatonin concentrations in these patients . u Th s, it is hormone that plays a key role in regulating energy intake possible to assume that an increased level of testosterone in and expenditure. It was shown in experiments that leptin girlswithAIS maybeassociatedwithadefectinmelatonin may stimulate osteoblastic differentiation in vitro,likely signaling. promoting the expression of osteoblastic related genes . Estrogen levels in AIS also appear to be important, Leptin can also act through hypothalamus augmenting sig- but the data are conflicting. Skogland and Miller [ 110]did nals that enhance osteocalcin excretion from osteoblasts not nd fi significant differences in blood levels of estradiol, that modulate glucose-insulin and weight homeostasis . prolactin, follicle stimulating hormone, or luteinizing hor- On theother hand,leptinisabletostimulate sympathetic mone between girls with AIS and controls, aged 7–17 years. neurons in the hypothalamus and indirectly inhibit bone Raczkowski alsoreportedonthe absenceofstatistically formation. This eeff ct may be diminished by administration significant differences in estrogen levels during the follicular of beta-adrenoblockers . To note, melatonin interacting and luteal phase between girls, aged 12–17 years, with right with insulin upregulates leptin expression by adipose cells thoracic scoliosis and slight lumbar functional scoliosis. . u Th s, it is possible to assume that a decreased level However, Kulis et al. [129, 130]havefound asignicfi antly of circulating leptin may be associated with an impairment lower level of estradiol and parathormone in girls with IS aged of melatonin signaling in adipocytes. Burwell et al.  11–14incomparisonwithhealthycontrols.Espositoetal. proposed a “double neuroosseous theory” of pathogenesis of also reported on lower blood content of 17𝛽 -estradiol and AIS in girls, which postulates that developmental disharmony progesterone in AIS girls with respect to control. Decreased expressed in spine and trunk between autonomic and somatic level of estradiol observed at the earlier pubertal period may nervous systems leads to AIS. eTh important component of reflect a maturity delay. On the contrary, Goldberg et al. [ 131] this theory is increased sensitivity of the hypothalamus to reported that menarche in girls with IS in the Irish popu- circulatingleptinwithbilateralasymmetryofthesympathetic lation was0.39years earlierthanthe national mean.Those nervoussystemresponse,whichcausesanasymmetryinaxial diagnosed at a younger age were generally taller than their skeletal growth and initiates the scoliotic spine deformity. peers, indicating that the growth spurt in girls with IS was A growth hormone-IGF axis plays a role as a modulator earlier. A study in Scandinavian girls found that menarche of these processes. eTh developmental abnormalities are occurs significantly later in girls with a thoracolumbar or a accompanied by osteopenia, intervertebral disc degeneration, double primary curve than in the control group. At the time of and platelet calmodulin dysfunction. However, the author menarche, the girls with a thoracolumbar or double primary noted that this double neuroosseous theory requires testing curveweresignicfi antlytallerthanthose in thecontrol group . . u Th s, some features of hormonal regulation observed in A decreased estrogen level corresponds with a decrease in patients with IS may be initiated by different predominant bone mineral content (BMC), bone mineral density (BMD), factors, the changes in hormonal regulation play a signicfi ant lower osteocyte count, and lower trabecular thickness in role in the morphological structure of bones, vertebrae end- thetrabecularboneingirls with IS [133, 134]. Estrogen plates, and intervertebral discs contributing to a faster growth decfi iency leadstoanincreaseinboneremodelingin spurt, increased bone remodeling, decreased bone mineral which resorption overtakes formation through an increase density, and spine slenderness. er Th efore, corresponding in immune function, which culminates in an increased attributes maybeobservedinthe vertebraeendplates and production of tumor necrosis factor (TNF) by activated T IVD structure at the different levels of the scoliotic spine. cells. TNF increases osteoclast formation and bone resorp- tion both directly and by augmenting the sensitivity of maturing osteoclasts to the essential osteoclastogenic factor 3.10. Genetic Factors. Study of AIS in twins demonstrated RANKL . The mechanism by which estrogen plays a that monozygous twins have a significantly higher rate of role in IS may be linked with calmodulin. There is evidence concordance and correlation between curve development that calmodulin decreases the estrogen binding capacity and progression than dizygous twins [35, 147], suggesting a of estrogen receptors . It is possible that increased genetic predisposition to the disease . Potential candi- intracellular levels of calmodulin that result from impaired date genes have been previously identified [ 149–151]. Single melatonin signaling may contribute to decreased eects ff of nucleotide polymorphisms (SNPs) of different genes have estrogen while the estrogen level in blood is normal in been defined as having association with susceptibility or patients with IS. Decreases in parathormone in patients with progression of AIS during last decade, Table 1.Theseinclude Advances in Orthopedic Surgery 7 Table 1: Genes showed an association with AIS. # Identified Genes Population tested Published by Genes potentially associated with IS: 1 Analysis of the Human Cytogenetics Database Brewer et al., 1998  2p15-13, 6q13, 15q12 GenesassociatedwithIS: A genome-wide search in one large family (7 2 Wise et al., 2000  6p, distal 10q, 18q affected members). GenesassociatedwithIS: 19p13.3 (D19S216; D19S894; D19S1034) Seven families with AIS consisting of 25 3 D2S160-D2S347-D2S112 Chan et al., 2002  aec ff ted members were studied. No linkage was found with markers on the X chromosome GenesassociatedwithIS: 202 families with at least 2 individuals with IS 4 Xq23 (GATA172D05) in 15% of studied families Justice et al., 2003  (total of 1198 individuals were studied). stratified for genetic heterogeneity GenesassociatedwithIS: Population of 81 trios (daughter/son affected by 5 Montanaro et al., 2006  Matrilin-1 (MATN1) gene polymorphism, 1p35 IS and both parents). GenesassociatedwithIS: 222 cases (90% female) Matrilin-1 (MATN1), 750 controls (88% female) 6 Chen et al., 2009  rs1149048, 1p35 adolescents Association with AIS susceptability Chinese population GenesassociatedwithIS: 166 cases (80% female) Matrilin-1 (MATN1), 126 controls (100% female) 7 Bae et al., 2012  rs 1065755, 1p35 Adolescents Association with curve type Korean population GenesassociatedwithIS: 25 cases (AIS) Matrilin-1 (MATN1) 8 25 controls Wang et al. 2009  Association with curve severity and decrease of plasma Chinese population mtrilin-1 level 1819 cases (AIS) 25934 controls Japanese population, GenesassociatedwithIS: 743 cases (AIS) 9 G-protein-coupled receptor 126 (GPR126), rs6570507, 1209 controls Kou et al., 2013  6q24.1 Chinese Han population, 447 cases (AIS) 437 controls European ancestry population GenesassociatedwithIS: Genome-wide scan follow-up study of 52 10 CHD7 gene polymorphism, families with history of IS (130 aeff cted Gaoetal.,2007 8q12 individuals). GenesassociatedwithIS: Initial screening (472 cases and 304 controls), Melatonin receptor 1B gene (MTNR1B), 11 and separate replication test (342 cases and 347 Qui et al., 2007  rs4753426, controls) 11q21-q22 GenesassociatedwithIS: 12 Estrogen receptor𝛼 gene 304 girls with IS were tested. Inoue et al., 2002  XbaI, 6q25.1 (association with curve severity) GenesassociatedwithIS: 202 cases 13 Estrogen receptor𝛼 (ER𝛼 )gene Wu et al., 2006  174 controls XbaI,6q25.1(maybeassociatedwitharisk of AIS) GenesassociatedwithIS: 14 5 families with triple IS spine deformities Marosy et al., 2010  21 candidate genes on chromosomes 6 and 10 GenesassociatedwithIS: 147 cases (53% AIS, 47% unaeff cted sisters) 15 Estrogen receptor𝛼 (ER𝛼 )gene, 104 controls (no AIS) Esposito et al., 2009  6q25.1 Age 13–19 years 8 Advances in Orthopedic Surgery Table 1: Continued. # Identified Genes Population tested Published by GenesassociatedwithIS: 30 AIS cases (6 male, 24 female) Calmodulin 1 (CALM1) gene 16 30 controls (age- and gender-matched) Zhuang et al., 2007  Melatonin receptor 1B (MTNR1B) gene, rs1562444, Chinese population 11q14.3 GenesassociatedwithIS: 67 cases (double curve patients) 17 Zhao et al., 2008  Estrogen receptor 1 (ESR1) gene rs2234693, 6q25.1; 100 nonscoliotic controls 67 cases (double curve patients) Calmodulin 1 (CALM1) gene: Zhao et al., 2008  18 100 nonscoliotic controls rs12885713, rs5871, 100 AIS cases 14q24-q31 Zhao et al., 2009  100 Controls GenesassociatedwithIS: 218 cases (176 female; 42 male) Estrogen receptor𝛽 gene−458T>C site polymorphisms 19 with AIS Zhangetal.,2009 of 14q23.2. 140 healthy controls. Association with AIS in females and with curve severity. GenesassociatedwithIS: 389 cases (336 female; 53 male) G-protein coupled estrogen receptor 1 (GPER1), 338 controls (289 female; 49 male) 20 rs3808351, rs10269151, 426655s3, Peng et al., 2012  Age: 10–19 years 7p22.3 Chinese Han population Association with curve severity A three-generation family of Italian ancestry GenesassociatedwithIS: that included 11 members aec ff ted by IS BaghernajadSalehietal., 21 D17S947–D17S798 Genome scanning was performed with 358 2002  17p11 microsatellite markers. GenesassociatedwithIS: The osteoprotegerin gene 1181 G → C polymorphism 22 198 females with AIS were tested. Eun et al., 2009  was associated with the bone mineral density of the lumbar spine in females with AIS, 8q24. GenesassociatedwithIS: 103 AIS patients (Cobb angle> 30 ), and 107 The tryptophan hydroxylase (TPH1) rs10488682, 23 nonscoliotic controls. All subjects were Han Wang et al., 2008  11p15.1. Chinese 10–20 years of age. Association with susceptibility to AIS GenesassociatedwithIS: The tryptophan hydroxylase (TPH1), 312 AIS cases (90 progressive, and 222 no rs10488682, 11p15.1. progression) 24 The estrogen receptor 𝛼 (ER𝛼 ) Xu et al., 2011  Brace treatment rs9340799, 6q25.1 Chinese population Association with cure progression and success of brace treatment Gene associated with IS: 103 AIS cases 25 5-hydroxytryptamine (serotonin) receptor A (HTR1A), 108 controls (age- and gender-matched) Wang et al., 2010  rs6294, 5q12.3 Chinese population GenesassociatedwithIS: Fibrillin 3 (FBN3), rs35579498, rs7257948 273 AIS patients, aged 10–18 years 26 19p13 287 control-healthy age-matched female Cao et al., 2008  Association with curve occurrence and progression in adolescents. AIS Gene associated with IS: 53 patients with AIS and 206 nonscoliotic 27 Metalloproteinase-3 (MMP3) promoter gene Aulisa et al., 2007  controls. Age was not specified. 11q22.3 190 AIS cases Gene associated with IS: 190 controls 28 Huang et al., 2011  Metalloproteinase-9 (MMP9), rs2250889, 20q13.12 Female Chinese Han population Gene associated with IS: 53 patients with AIS and 206 nonscoliotic 29 Interleukin-6 ( IL6) promoter gene Aulisa et al., 2007  controls. Age was not specified. 7p21-p15 Advances in Orthopedic Surgery 9 Table 1: Continued. # Identified Genes Population tested Published by 198 AIS cases (female) Gene associated with IS: 120 controls (female) 30 Interleukin-6 ( IL6) Lee et al., 2010  Age: 11–14 years Association with bone mineral density in AIS Korean population 529 cases (AIS, female 100%) Gene associated with IS: 512 controls (female 100%) 31 Inrleukin-17 receptor C (IL-17RC) gene, Zhou et al., 2012  Age: 11 to 18 years rs708567, 3p.25.3. Chinese Han population Gene associated with IS: 32 Neural adhesion molecules 419 AIS families Sharma et al., 2011  CHL1,rs1400180,3p26.3 1376 cases (AIS, female 100%) Gene associated with IS: 11297 controls (female 100%) Takahashi et al., 2011  Japanese population; 33 Ladybird homeobox 1 (LBX1) rs11190870, 10q24.31 300 cases (AIS, Cobb> 30 degree) 780 controls Fan et al., 2012  Southern Chinese population; 513 cases (AIS) 440 controls Gaoetal.,2013 Chinese Han population 198 Korean girls 11–13 years of age with AIS, Gene associated with IS: Suhetal.,2010 34 and 120 age-matched healthy girls (control). Vitamin D3 receptor gene polymorphism (VDR Bsml), Xia et al., 2007  164 females 9–20 years of age with AIS, and 122 12q13-14. age-matched healthy girls (control) Associated with low bone mass and low bone mineral density at the lumbar spine in girls with AIS Gene associated with IS: 500 cases (AIS) 35 Histone methyltransferase (DOT1L), Maoetal.,2013 497 controls rs12459350, 19p13.3; Gene associated with IS: 500 cases (AIS) 36 Chromosome 17 open reading frame 67 Maoetal.,2013 497 controls (C17orf67), rs4794665, 17q22. Gene associated with IS: 362 cases Neurotrophin 3 (NTF3) gene, 37 377 controls Qiu et al., 2013  rs11063714, 12p13 Chinese Han population Association with curve severity Gene associated with IS: 38 SH3GL1 protein-coding gene, 214 IS cases (68 male, 146 female) Yang et al., 2012  19p13.3 Gene associated with IS: Lysosomal protein transmembrane 4 beta (LAPTM4B), 68 AIS cases rs2449539, 8q22.1 39 35 controls (age- and sex-matched) Moon et al., 2013  Insulin-like growth factor 1 (IFG1), rs5742612, 12q23.2 Korean population Association with susceptibility to AIS and curve severity a polymorphism of the promoter of melatonin receptor 1B of the choane, retardation of growth and/or development, gene (MTNR1B) that was revealed in Chinese population  genital, and/or urinary abnormalities, and ear abnormalities corresponding with previously revealed impairment of the and deafness). It was hypothesized that milder variants of the melatonin transduction pathway . However, this result CHD7 polymorphism could underlie IS susceptibility . was not replicated in Japanese and Caucasian A link between matrilin-1 gene polymorphism (MATN1) and populations. An association of AIS was also found with the AIS has been found in European , Chinese [156, 157], and CHD7 gene (chromodomain helicase DNA-binding protein Korean populations butwas notreplicatedinJapanize 7 gene) . Splicing mutations within coding exons of population . Wang et al.  noted that MATN1 CHD7 have been identified in a majority of patients with polymorphism in AIS corresponds with decrease of plasma CHARGE syndrome (coloboma of eye, heart defects, atresia matrilin-1 levels. Matrilin-1 was previously named cartilage 10 Advances in Orthopedic Surgery matrix protein (CMP) and is mostly found in cartilage. population. es Th e ndin fi gs were not replicated in Japanese CMP is a bridging molecule that connects matrix compo- population . It has been proposed that a disturbance in nents in cartilage to form an integrated matrix filamen- proteoglycan (PG) synthesis and formation in the vertebral tous network . Biglycan/matrilin-1 or decorin/matrilin-1 growth plateisabasiccause of IS.Itwas suggestedthataggre- complex acts as a linkage between collagen VI microb fi rils can gene expression was significantly decreased in cultivated and aggrecan or alternatively collagen II . u Th s, a chondroblasts from patents with IS . However, Marosy defect of CMP/matrilin-1 molecules may cause a significant et al.  showed the lack of an association between the impairment of the cartilage ultrastructure. Genetic variants aggrecan gene and familial IS, but other potential candidate of GPR126 gene showed association with AIS in Japanese, genes were revealed on 15q25-26. To note, b fi rillin-1 (FBN1) Chinese Han, and European-ancestry populations . This gene, which is associated with Marfan syndrome, is located gene encodes G-protein-coupled receptor 126 required for nearby (at15q21.1). Nevertheless, an association between a normal differentiation of promyelinating Schwann cells and polymorphism of the FBN1 gene and AIS was not found axons myelination . This gene is highly expressed in . Twenty-one candidate genes on chromosomes 6 and 10 cartilage  and probably is involved in regulation of the were found in families with triple IS spine deformities . cAMP level in cells  and development of spinal cord Salehi et al. reportedonthe link betweenfamilialISand . Data on the role of X chromosome in the pathogenesis 17p11 (D17S947-D17S798) gene polymorphism. These protein of IS are contradictory. Justice et al. reportedonthe genes play a role in glycoproteoglycan sulfation, the process association between familial IS and a polymorphism of X that is important for the organization of osteoligamentous chromosome particularly GATA172D05. This region includes structures. A significant association was found between several loci whose functions have been related to cellular the osteoprotegerin (OPG) gene polymorphism and bone interactions within the extracellular matrix of neural tissue mineral density of the lumbar spine in female with AIS and a chordin-like protein, which is known to be essential . OPG is a cytokine that is a member of the tumor to the correct patterning of the zebrafish axial skeleton necrotic factor superfamily, which inhibits the production through bone morphogenetic proteins signaling. The genes of osteoclasts and thus indirectly stimulates bone modeling. that encode two of the collagen type IV alpha chains have eTh OPGgenepolymorphisms mayindirectlystimulate also been mapped to this region. However, evidence of the osteoclastogenesis and bone remodeling. Wang et al.  X chromosome polymorphism was only found in 15% of the have found a significant association between a tryptophan studied families, which had X-linked dominant inheritance. hydroxylase (TPH1) gene polymorphism and susceptibility Chan et al.  did not nd fi any link between the X- to AIS in Chinese population. Xu et al. suggested that chromosome polymorphism and IS but revealed a significant the TPH1 gene SNP is associated with the risk of curve association between the abnormal phenotype of the distal progression. The TPH1 is involved in the synthesis of the short arm of chromosome 19p13.3 and AIS. Within this neurotransmitter serotonin from tryptophan, which then can region, there are more than 70 possible genes expressed be transformed to melatonin. u Th s a polymorphism of this in chondrocytes, osteoclasts, muscles, or tendon that could gene can contribute to reduced synthesis of both serotonin be potential candidate genes for IS. In particular, fibrillin-3 and melatonin. However, this SNP was not replicated in gene is in this region. Polymorphisms of this gene may be Japanese and Caucasianpopulations.Itwas shown associated with body height of the AIS patients, or occurrence that a MMP-3 promoter gene polymorphism is significantly and progression of AIS . Data on the association of the associated with AIS . But this nding fi was not replicated estrogen receptor gene polymorphism with susceptibility to in Chinese population . The MMP-3 relates to the matrix IS are contradictory. Inoue et al. reportedonthe associ- metalloproteinasefamilythatisinvolvedinthe breakdownof ation between estrogen receptor𝛼 (ER𝛼 )genepolymorphism extracellular matrix, in particular degrading of fibronectin, and curve severity. Wu et al.  confirmed the association collagens III, IV, IX, and X, and cartilage proteoglycans and between the ER𝛼 gene polymorphism and AIS. Xu et al. tissue remodeling, as well as in disease processes, such as  suggested that the ER𝛼 SNP is associated with curve arthritis and metastasis. An IL-6 (interleukin 6) promoter progression. These findings could not be replicated by Tang gene polymorphism was also reported as having association et al. . However, Zhao et al. reportedonstatistically with AIS , in particular, bone mineral density in AIS significant associations between polymorphism of the ER 𝛼 patients . The IL-6 is a cytokine with a wide variety and calmodulin-1 (CALM1)  genes with susceptibility to of biological functions. It plays an essential role in the AISand thetypeofscoliotic curvature. Esposito et al. final differentiation of B-cells into Ig-secreting cells. This identified four ER 𝛼 gene polymorphisms in AIS. In addition, protein is primarily produced at sites of acute and chronic Zhang et al.  reported an association between SNP of inflammation, where it induces a transcriptional inflamma- the estrogen receptor𝛽 (ER𝛽 ) gene with AIS susceptibility tory response through corresponding receptors. This suggests and curve type and severity in females. On the contrary, an involvement of the immune system and inflammatory Takahashi et al.  did not nd fi any association between processes in the pathogenesis of AIS. However, no link these estrogen receptor genes and susceptibility to AIS or between IL-6 and AIS was found in Chinese population . curveseverityinthe Japanese population.Itwas reported Instead, in Chinese population, an association between the that polymorphism of G-protein-coupled estrogen receptor interleukin-17 receptor C (IL-17RC) gene polymorphism and (GPER)  and neurotropin 3 (NTF3)  genes has sig- the susceptibility to AIS was shown . The Il-17RC pro- nificant association with curve severity in AIS in Chinese Han motes the production of proinflammatory cytokines such as Advances in Orthopedic Surgery 11 TNF𝛼 ,IL-1𝛽 ,andIL-6. Mor ´ ocz et al.  demonstrated 3.11. Biomechanical Factors. Biomechanical factors play a that SNP of such genes as BMP4, Il6, leptin, MMP3, and significant role in the progression of scoliosis. A vicious cycle of asymmetrical loading has been hypothesized to explain MTNR1B may not have significant association with AIS, if they were tested separately. However, combinations of these this effect. It was suggested that increased compression on the concave side of the curve decelerates growth, while genes SNP have significant association with susceptibility reduced loading on the convex side accelerates growth to AIS in the Hungarian population. It was reported that according to the Hueter-Volkmann’s law and creates a larger a vitamin D receptor (VDR) gene SNP is associated with deformity [1–3, 204, 205]. Today, these phenomena may decreased bone mineral density, in particular of the lumbar be explained by the eeff cts of mechanotransduction, which spine in girls with AIS (Korean population) [189, 190]. The include intracellular and extracellular signaling factors such VDR are expressed in cells of different tissues, including as mechanosomes, corresponding genes, nitric oxide (NO), bone and the parathyroid gland. Vitamin D is involved in the cAMP, gene encoding enzymes, bone morphogenic proteins regulation of parathormone secretion . u Th s, this finding (BMP)1and4,and growth factorssuchasIGF-1, IGF- corresponds with decreased levels of parathormone revealed 2, vascular endothelial growth factor (VEGF), and trans- in girls with IS . However, Chen et al. did not forming growth factor-𝛽 (TGF-𝛽 ), which act via autocrine 1 1 find any association between the VDR gene polymorphism and paracrine mechanisms [206–208]. Signal transduction and bone mineral density in Chinese AIS girls. Variants near pathways such as IGF-1 may interact with estrogen in LBX1 gene encoding ladybird homeobox-1 have significant the proliferative response to mechanical strain . An link with AIS in Japanese  and Chinese populations interaction between different anabolic intracellular pathways [193, 194]. The LBX1 encodes transcription factor required may enhance the upregulation of these signaling pathways, for the development of interneurons in the dorsal horn of ultimately leading to the cellular response on mechanical thespinalcordand migrationand developmentofmuscle loading . Experimental studiesshowthatfor normal precursor cells for limb muscles, diaphragm, and hypoglossal bone modeling, bone strain should not exceed 2 MPa (MPa- 6 2 cord . The CHL1 gene was recognized as a candidate megapascal = 10 newtons/m ). If mechanical strain exceeds gene linked with susceptibility to AIS . This gene encodes 60 MPa, then microscopic fatigue damage and a decrease family of neural cell adhesion molecules that may be involved in bone growth may occur . Unfortunately, there is a in signal transduction pathways . Polymorphism of paucity of data related directly to the quantitative in vivo other two genes DOT1L encoding histone methyltransferase assessment of strain at the surface of the human vertebrae and C17orf67 (chromosome 17 open reading frame 67) are endplates and the association between strain and the mor- shown as linked with susceptibility to AIS . The histone phological and ultrastructural characteristics of the vertebrae methyltransferase DOT1L plays a complex role in cartilage endplates and discs in patients with IS, especially in the biologyand maybeassociatedwithosteoarthritis[163, 196]. upright position [211, 212]. Meir et al.  reported results of Characteristics of the protein that is encoded by C17orf67 hydrostatic pressure measured across the IVD in recumbent are not studied well . Other genes SNPs that have been anaesthetized scoliotic patients during surgery. It was shown reported as having association with AIS are SH3GL1 , that intradiscal pressure and stress in scoliotic discs are LAPTM4B , IFG1 , MMP9 , HTR1A , and abnormal and have higher hydrostatic pressure (0.25 MPa) TIMP2 . than those measured in nonscoliotic discs (<0.07 MPa). Axial Biotech Inc.  has developed a test to iden- Stress in the concave annulus was greater than in the convex tify patients with low risk of scoliotic curve progres- annulus, indicating asymmetric loading. The authors noted sion using 53 genetic markers. Published results suggested that without the presence of muscle activity and horizontal that the test has high negative predictive value (97%– positioning of the patients, it is difficult to explain this finding 100%), but low positive predictive value (8%–25%) . from the point of view of the “vicious cycle” hypothesis. It means that cases with high risk of scoliotic deformity progression can be underdiagnosed by this test. The test showed lack of predictive value in Japanese population 4. Morphological and Ultrastructural Features . of Scoliotic IVD and VEPh In summary, published data concerning association between gene polymorphism and AIS are heterogeneous and 4.1. Disc Cells and Extracellular Matrix Features. It was have limited replicability. We may assume that AIS may suggested that asymmetry in mechanical loading is the have different patterns of genetic determinants depending on main factor that leads to morphological changes in scoliotic the ethnic population. Combinations of these determinants IVD and VEPh. eTh effects of mechanotransduction are probably predispose individuals to the disease. Defects in the important components in the response of bone and cartilage molecular structure of different proteins, caused by genetic to mechanical load. Mechanotransduction pathways involve polymorphism, may lead to different ultrastructural features specific cytoskeletal components, such as vimentin and actin. at different systems and tissues of the body, including the Johnson and Roberts  compared the presence of such CNS, hormonal regulation, the immune system, connective cytoskeletal components as phalloidin-labeled filamentous tissue, bone, cartilage, ligaments, and muscles, which form actin (F-actin) and vimentin in the disc cells of patients specicfi conditions for the spine curve triggering and progres- with scoliosis, in subjects without disc pathology, and in sion. subjects with degenerative disc diseases. F-actin-positive cells 12 Advances in Orthopedic Surgery appearing stellate or dendritic were observed in the outer feature, were seen in scoliotic discs but not in age-matched annulus of scoliotic discs. Such cells were not seen in the controls. However, based on these data it is impossible outer annulus fibrosus of nonscoliotic or degenerative discs. to determine whether the finding of a sparse elastic fiber F-actin appeared more prominent on the convex side of the networkinthe IVDofpatientswithISisaprimaryor scoliotic curve than on the concave side, not corresponding secondary factor. Akhtar et al. showedthatinthe with the putative response. eTh authors suggested that cells in degenerated regions of scoliotic IVDs there was a disruption scoliotic discs tend to change phenotype in comparison with of collagen and elastic fibers accompanied by losses of keratan nonscoliotic discs. This study had considerable limitations sulfate (KS) proteoglycan, and degeneration of elastic fibers (see Table 2) necessitating further investigation. Ford et al. that was accompanied by the loss of𝛼 -elastin. KS-bearing  used transmission electron microscopy and immunos- proteoglycan (lumican or b fi romodulin) is closely associated taining markers and revealed that cells of scoliotic discs with the lamellar organization of collagen b fi ers and elastic exhibited a healthy appearance and abundant endoplasmic fibers in the IVD. It was hypothesized that impaired cellular reticulum, which indicated a high level of secretory activity, metabolism of lumican and/or brom fi odulin can contribute while proliferative activity was decreased. Specimens for this to the development of scoliotic spine deformity. As specimens study were taken from the anterior annulus of the discs, thus in this study were taken from the medial parts of the IVDs, asymmetrical load probably did not impact the results. asymmetrical axial load did not impact the results. u Th s, this Bertram et al.  demonstrated that chondrocyte- finding probably reflects systemic features of scoliotic cells. typical extracellular-matrix gene expression was higher Stern et al.  demonstrated significantly higher synthesis in scoliotic IVDs than in the normal spine. Histological of deoxyribonucleic acid, proteoglycan, and hydroxyproline analysis showed mild degeneration of the IVDs, includ- in cells from scoliotic disks in comparison with cells taken ing minor granular changes, clesft and tears, and mucoid from osteochondrotic and herniated discs. There was no matrix degeneration that was accompanied with accelerated evidence of enhanced senescence (physiologic aging) or anabolic matrix metabolism, which included higher extra- apoptosis  of IVD cells in patients with IS in comparison cellular matrix gene expression of collagen type II, biglican, to those with neuromuscular scoliosis or disc degenerative collagen type XI, collagen type XII, aggrecan, lumican, diseases. Unfortunately, a comparison between IS disc cells chondromodulin-I precursor, and decorin. Antoniou et al. and normal age-matched disc cells was not performed in  revealed a decrease in the total collagen content in the these studies. IVD degeneration correlated with the level scoliotic annulus and endplate regions. Glycosaminoglycan of matrix metalloproteinases (MMP), which contribute to content was also decreased in the scoliotic endplates and extracellular matrix degrading and tissue remodeling and are nucleus regions. However, the total protein level was sig- involved in inflammatory reactions [ 228]. The MMP level nicfi antly elevated. Water content was considerably lower in was asymmetric and prevailed at the convex site of IVDs in the scoliotic annulus and endplate regions. Levels of marker patients with AIS . for type II collagen synthesis were higher in the nucleus, In summary, the most important features of the IVD annulus, and endplate regions of scoliotic discs than in the in IS are as follows: (1) increased synthetic and decreased corresponding regions of normal discs. By contrast, the pres- proliferative cells activity; (2) changes and asymmetry of ence of total denaturated collagen was significantly elevated collagen synthesis and degrading; (3) increased synthesis of inthenucleusofnormaltissueascomparedtoscoliotictissue. proteins; (4) impairment of collagen turnover that results in eTh authors suggested that these scoliotic changes are due to failure of the synthesized extracellular matrix components an altered and ineecti ff ve synthetic response to a pathologic to organize into a normal lamellar structure; (5) decreased mechanical environment. eTh se results correspond with the water content and increased hydrostatic pressure. Initial n fi ding that proteoglycan molecules in patients with AIS genetic determinants probably comprise the basis of these contained more protein and less carbohydrates than the IVD features, which may then be significantly modulated proteoglycans of normal tissue . It was shown that a by the mechanical environment and other factors during chondroadherin level was lower at the concave site of the disease manifestation. Overall these microstructural features scoliotic discs than at the convex side, suggesting changes in decrease the ability of scoliotic discs to tolerate load and matrix homeostasis . He et al. showedthatpatients contribute to disc wedging and Schmorl’s nodes occurrence. with AIS had significantly more type I and type II collagen This is more evident at the apex of the lumbar curvature on the convex side of IVDs compared with the concave side. whereloadishigher, whilewedging of thevertebral body Similar results had previously been obtained by Roberts et prevails at the apex of the thoracic curvature [204, 205, 229]. al. . They also pointed out that staining patterns for collagen types III, VI, and IX were different in scoliotic IVDs in comparison with nonscoliotic IVDs . Gene expression 4.2. Vertebrae Endplate Features. Roberts et al. pointed of type X collagen, which was associated with hypertrophic out that the prevalence and extent of calcification in the changes and cartilage mineralization, was revealed mainly cartilage endplate of the scoliotic specimens were the most at the concave side of the apical disc in patients with IS striking finding of their study. Calcification appeared to start . Yu et al. showedthatinscoliotic IVD(AISand at one or both ends of the individual cells before it encom- neuromuscular scoliosis), the elastic b fi ers were sparse, and passed the cell and became more widespread throughout the collagen and elastic fiber networks were disorganized with a matrix. It was prominent in the cartilage endplate nearest the loss of lamellar structure. Cell clusters, a typical degenerative anterior rim. Calcification may also expand into the IVD. Advances in Orthopedic Surgery 13 Table 2: Morphological and ultrastructural studies. The main limitations of the # Findings Objects/Materials Method Authors study (1) Small amount of F-actin-positive cells were specimens. observed in the outer (2) Statistical analysis was anulus of scoliotic discs and Specimens of 13 human Morphology of IVD cells not performed appeared stellate or intervertebral discs: was examined using (3) Studied subjects were Johnson and dendritic, rather than Normal—3; confocal microscopy and 1 not matched by age and Roberts, 2003 bipolar and fibroblastic. Low back pain—4; labeling of such gender.  F-actin appeared more Spondylolisthesis—3; cytoskeleton components (4) Specimens were not prominent on the convex Scoliosis—3 as F-actin and vimentin. matched by the spine level. side of the scoliotic curve (5) Type of scoliosis was than on the concave side not specified eTh anterior annulus tissue Cellsfromanterioranulus of discs: (1) Subjects gender was not of scoliotic discs had Scoliotic—5 (aged 16–26); Histology and transmission taken into consideration. Ford et al., 2 increased secretory activity Degenerative—5 (aged electron microscopy with (2) Statistical analysis was 2002  and decreased proliferative 43–56); immunostaining markers. not performed. activity. Prolapsed discs—5 (aged 33–52) Study groups: Morphologic disc Idiopathic scoliosis (11 degeneration in IS was female and 5 male aged associated with stronger 10–22 years); anabolic matrix Patients with acute trauma metabolism. (2 female, and 5 male aged (1) Studied subjects were Higher mRNA expression Histological examination. Bertram et 3 28–55); not matched by age and of extracellular matrix Gene expression analysis. al., 2006  Autopsy control gender. molecules like collagen II, adolescents (4 male and 4 aggrecan, biglican, decorin, female aged 8 to 17 years); lumical, and Autopsy control adults (7 chondromodulin was male and 3 female aged revealed. 47–77 years) Higher collagen Type II (1) The scoliotic tissue was synthetic levels and Specimens of IVD and Discs and endplates were analyzed mainly at the increased total protein vertebrae endplates: analyzed for their water, convex and central side of content with no matrix (i) 15 scoliotic (female) collagen, proteoglycan, and thediscwhere thetissueis Antoniou et 4 turnover. Scoliotic changes aged 11–15 years; protein content. experiencing tension and al., 2001  are due to an altered and (ii) 17 normal control Biochemical methods were not compressive force ineecti ff ve synthetic subjects (no details) used. (2) Control group was not response to a pathologic clearly identified. mechanical environment. Studied subjects: Cells obtained from IS—6 patients (mean Cultures of disc cells were (1) Gender of the studied scoliotic discs showed age—24.4 years); studied. subjects was not taken into higher synthetic activity Osteochondrosis—6 Deoxyribonucleic acid Stern et al., 5 consideration. than cells from patients (mean age 42.8 content, hydroxyproline 2004  (2) Studied subjects were degenerative and herniated years); content, and proteoglycan not matched by age. discs. Disc herniation—6 patients synthesis were determined. (mean age 35.2 years) In scoliotic discs, elastic Studied subjects: Micrographs of the sections fibers were sparse, and the IS—3 female (age 12–22 of IVDs were examined by collagen and elastic fiber years); polarized light to visualize networks were (1) Small amount of cases Neuromuscular—3 female collagen organization. The disorganized with loss of and controls. Yu et al., 2005 6 (age 14–16 years); elastic b fi er network was lamellar structure. Cell (2) Statistical analysis was  Control—2 (1 female with visualized clusters (degenerative not performed. spinal tumor aged 12 years; immunohistechemically or feature) were seen in 1malewithtraumaaged17 by histochemical staining scoliotic discs but not in years) with orcein. age-matched control discs. 14 Advances in Orthopedic Surgery Table 2: Continued. The main limitations of the # Findings Objects/materials Method Authors study Specimens from medial (anterior, central and (1) Small case and control In scoliosis, impaired Studied subjects: posterior) parts of L1–L3 groups. regulation of collagen IS—3 female patients (13, discs were studied. (2) Cases and controls were Akhtar et al., 7 fibrillogenesis by lumican 15, and 17 years old); Ultrastructural relations not matched by gender and 2005  or b fi romodulin may result Normal control—2 male among keratan sulfate age. in lamellar structure. (20, 24 years old) proteoglycan,𝛼 -elastin, (3) Statistical analysis was collagen fibers, and elastic not performed. fibers were studied. Proteoglycan and water (1) Case and controls were content were reduced in Studied subjects: not matched by age and scoliotic discs, particularly Scoliosis—20 patients gender. toward concavity of the including 15 with IS, 4 with (2) Cases with IS and curve. eTh distribution of congenital, and 1 with The morphology and congenital scoliosis were some collagen types unknown type. Age: 3–42 composition of the IVD not analyzed separately. Roberts et al., differed in scoliotic discs. years (mean—14.4). Gender and vertebrae cartilage (3) Specimens were not 1993  Calcification of the was not indicated. endplates were studied matched by the spine level cartilage endplates and Control—12 subjects. Age (T6–T10 for scoliosis; adjacent discs was revealed 17–83 (mean—58.1). L1–L5 for controls). in scoliosis. Gender was not identified. (4) Statistical analysis was not performed. (1) Small amount of cases Studied subjects: Specimens from scoliotic and controls Scoliosis (AIS)—7 patients subjects were taken during (2) Cases and controls were (5 female and 2 male), age A chondroadherin level surgery (1 T9/T10, 3 T12/L1, not matched by age Haglund et 14–17 years. 9 decreased at the concave and 3 L1/L2 discs). (3) Cases and control al., 2009 Control—2 nonscoliotic site of scoliotic discs Control specimens were specimens were not  subjects aged 29 and 87 obtained during autopsy matched by the spine level years. Gender was not (2-L4/L5 discs) (4) Statistical analysis was specified. not performed. The author noted that most studied patients with scoliosis growth factor (bFGF) was higher on the concave side in had not reached skeletal maturity at the time of the study. patients with AIS, while expression of the core protein of Therefore, endochondral ossification should be ongoing in proteoglycan was higher on the convex side [233, 234]. TGF𝛽 epiphyseal regions, such as the cartilage endplate. Calcifica- relates to the family of bone morphogenetic proteins and reg- tion of the IVD has also been described in healthy children, ulates growth and proliferation of cells. TGF𝛽 1actsthrough which resolved later in life. To note, cases and controls were corresponding receptors and mediates a transcriptional acti- not matched by age and gender in that study. vation. In particular, it regulates collagen type II gene expres- There was evidence that the proliferative and hyper- sion which suggests an important role in the repair process trophic chondrocytes in the anterior column of AIS patients during early IVD degeneration. However, this effect depends were more active than those on the posterior column [230, on whether the cells are fully differentiated or undergoing 231]. These features seem to be more evident in patients with phenotype loss . To note, melatonin stimulates TGF𝛽 1 AIS than those with congenital scoliosis. It has also been activity , thus, an impairment in melatonin signaling shownthatinAIS theproliferative potentialand apoptosis may modify this eeff ct in patients with IS. FGFs are a family ratios of chondrocytes in the proliferative and hypertrophic of growth factors involved in wound healing and embryonic zone in the convex side were significantly higher than in development. One of the most important functions of bFGF is theconcave side,particularlyinthe apical vertebralgrowth the promotion of endothelial proliferation and angiogenesis plate . Changes in proliferative activity of chondrocytes . But it is also known that excessive release of bFGF correlated with the radiographic data of the spine deformity. during loading and/or injury of the cartilage matrix may However, it was unclear whether these differences in pro- contribute to the onset or progression of osteoarthritis. This liferation were theprimary causeorweredue to secondary changes. eTh authors suggested that these n fi dings may be pathological role may be related to the ability of bFGF to secondary and result from mechanical causes. decrease proteoglycan synthesis and to antagonize the activity Expression of cell signaling factors is an important of anabolic growth factors in cartilage such as IGF-1 and BMP-7 and stimulate matrix metalloproteinase-13, which marker of cell activity. It was found that expression of transforming growth factor𝛽 1(TGF𝛽 1) and basic fibroblast is a matrix catabolic cartilage-degenerative enzyme . Advances in Orthopedic Surgery 15 Experimental data suggest that melatonin modulates the foundbetweentheappearanceofmelatoninsignalingimpair- effects of bFGF and inhibits bFGF gene expression [ 239]. ments in osteoblasts and lymphocytes allows a wider use of Administration of melatonin reduced the cartilage endplate this approach for predicting curve onset and progression, vascularity of degenerated intervertebral discs. It may have especially during earliest stages of the disease . Another a stimulative eect ff on bone formation. However, bFGF and intriguing finding is polymorphism of estrogen receptors TGF𝛽 1 are involved in the mechanisms of mechanotransduc- genes, which suggests defects in estrogen signaling. The role tion. us, Th the effects of mechanotransduction and impair- of calmodulin signaling mechanisms in IS requires further ment of melatonin signaling pathways may overlap, making clarification. eTh immune system, including T and B cells, endplate cells more sensitive to mechanical impact. Increases may also play a role in pathogenesis of AIS. in (bFGF) correspond to the results of inflammatory endplate The data suggest that progressive, in particular, double changes, which are present at the concave apex in patients spine scoliotic deformity, should be associated with abnormal with AIS . IVD structure. IVD wedging in AIS begins or enhances The majority of published data in the field of morphology at adolescent growth spurt when body weight increases andultrastructureofIVD andVEPhinIShaveserious dramatically. eTh IVD wedging is most prominent in the limitations that make interpretation of the results dicffi ult. lumbar spine where axial loading is maximal. Markers of Some of these limitations are summarized in Table 2.Thereis VEPh cell activity at the concave and convex sides suggest that also a lack of data on the morphological and ultrastructural strain at the concave side is probably not enough to reduce appearance of in infantile and juvenile IS. cell proliferation during the beginning of curve progression. u Th s, earlier wedging of vertebrae may be explained by the prevalence of a laterally directed appositional bone growth at the concave side. If appositional bone growth is also directed anteriorly or posteriorly, it may cause a rotational component 5. Discussion of the deformity. This appositional growth results from the Our literature review supports the theory of a multifactorial interaction of the vertebrae endplate with the outer annulus bfi rosusofthe adjacent IVD, whichisalsowedged. This etiology for IS. The different hypotheses highlight the diverse aspects of the etiopathogenetic mechanisms. Some of these IVD wedging is probably caused by changes in the disc’s mechanisms may be regarded as risk factors with different mechanical properties associated with sparse extracellular matrix and impaired lamellar structure. eTh se are caused by contributions in each disease case. This approach allows us to explain the wide variability of the clinical appearance in defects in bending proteins, which are synthesized by cells IS and hopefully predict disease occurrence and progression in the IVD and involved in spatial organization of cartilage in future. Combinations of different genetic determinants are molecules. A genetic predisposition for increased metallo- likely the main etiologic factor, which can be classified in two proteinase activity may also play role in accelerated disc main groups. First, polymorphism of genes that may cause degeneration. Asymmetrical ligament and muscular stretch cell signaling impairments in different tissues, including bone arealsoinvolvedinthe curveformation andparticularly and cartilage, and changes in hormonal regulation. eTh oret- in spine instability . Biomechanical factors modulate the curve formation by gradually forming the “vicious cycle” ically, combinations of these genetic features may contribute to such clinical appearances as skeletal and spinal overgrowth, effect. decrease in bone mineral density, delay of skeletal maturity We hypothesize that earlier treatment aimed at abnormal intervertebral discs in combination with reasonable spine and spine slenderness, and dysfunction of the central and autonomic nervous systems which predispose occurrence stabilization may help prevent adjacent vertebrae wedging and progression of the scoliotic spine curvature. eTh second and curve progression in those patients who are predisposed groups of genetic determinants are likely associated with to severe curvedevelopment.Theability to predictcurve systemic defects in the structure of connective tissue and onset and progression using risk factors assessment could significantly individualize and improve diagnosis and treat- cartilage and may be with changes in embryogenesis. They may be linked with such clinical appearances as instability ment outcomes in patients with IS. eTh rfi st steps in this field of spine, body asymmetry, and some concomitant congenital have already been taken, but further research is necessary to develop accurate and sensitive tools for risk assessment. abnormalities. There is a high probability that polymor- phisms of other genes that are associated with IS will be identified in the future. We may expect that the profile of IS genetic determinants significantly varies in different ethnic Conflict of Interests populations. eTh authors declare that there is no conflict of interests Serum content of such hormones as IGF1, testosterone, regarding the publication of this paper. estradiol, leptin, and parathormone as well as matrilin-1 can be used as additional prognostic markers during earlier pubertal period, especially in cases with spine curvature References <30 , which are the most difficult to predict. eTh melatonin signaling in AIS should be further studied, as this may  I. A. F. Stokes, R. G. Burwell, and P. H. Dangerfield, “Biome- allowfor thedevelopment of newdiagnosticcriteriafor chanical spinal growth modulation and progressive adolescent predicting curvature onset or progression. 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