Association Between IL-6 and MMP-3 Gene Polymorphisms and Adolescent Idiopathic Scoliosis

Aulisa, Lorenzo; Papaleo, Pierangelo; Pola, Enrico; Angelini, Flavia; Aulisa, Angelo Gabriele; Tamburrelli, Francesco Ciro; Pola, Paolo; Logroscino, Carlo Ambrogio

doi:10.1097/brs.0b013e31815a5943

Cited by 62 publications

(34 citation statements)

References 15 publications

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“…The combined sympathetic-hormonally-induced effects in the lower BMI subset produce mean Cobb angle and mean upper arm length asymmetry similar to, and mean AVR less than, the higher BMI subset (Figure 6) [46]. This postulate of an inverse relationship ignores other possible mechanisms that may contribute to curve progression common to each BMI subset, including osteopenia [88,278,279], biomechanical spinal growth modulation [80-82], intervertebral disc degeneration [45,342-351], and platelet calmodulin dysfunction [21,22,107]. …”

Section: Discussionmentioning

confidence: 99%

“…These are explained by the interaction of autonomic and somatic nervous systems in the spine and trunk compounded by any relative osteopenia of vertebrae [88,278,279], biomechanical spinal growth modulation [80-82], accelerated disc degeneration [45,342-351], and platelet calmodulin dysfunction [21,22,107]. Circulating leptin levels in AIS girls did not correlate significantly with Cobb angle [163,164].…”

Section: Discussionmentioning

confidence: 99%

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Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

et al. 2009

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Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

et al. 2009

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“…These all supported that CALM1 gene was likely to be a susceptibility gene associated with the etiology of AIS. Compared to the genetic susceptible factors, SNP sites would not produce an effect on the occurrence and development of diseases independently, they functioned together and intrinsically correlated with each other, haplotype was a reflection of genetic linkage, and, therefore, study of the haplotype could reveal the association between multiple SNPs loci and disease susceptibility [13–15]. Based on the haplotype analysis of the SNPs, frequencies were higher than 10%, and its haplotype distributions were different between case group and control group, and we got 1 positive haplotype: SNP8C-SNP01A-SNPl3C-SNPl4C-SNP02C-SNP3T-SNP4G-SNP05T-SNP011C; this again showed that CALM1 gene was possible to be a susceptibility gene of AIS.…”

Section: Discussionmentioning

confidence: 99%

“…Adolescent idiopathic scoliosis mainly affects girls in number and severity; several familial surveys of idiopathic scoliosis provided strong evidence that genetic factors have a role in this condition [7]. Single nucleotide polymorphisms (SNPs) in the genes for estrogen receptor a (ESR1) [8], estrogen receptor b (ESR2) [9], matrilin 1 (MATN1) [10], melatonin receptor 1B (MTNR1B) [11], tryptophan hydroxylase 1 (TPH1) [12], interleukin-6 (IL-6), and matrix metalloproteinase-3 (MMP-3) [13] have been reported to be associated with AIS predisposition. However, many scientists believe that there are still some more candidate genes that need to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

The Association Study of Calmodulin 1 Gene Polymorphisms with Susceptibility to Adolescent Idiopathic Scoliosis

Zhang

Qiu

2014

BioMed Research International

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Objective. Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to identify the relationship between the genotypes of the SNPs and the clinical phenotypes of AIS. Methods. 146 AIS patients and 146 healthy controls were enrolled into this case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in CALM1 gene were selected to determine the relationship between CALM1 gene and AIS predisposition. Case-only study was performed to determine the effects of these variants on the severity of the condition. Results. Three SNPs from 12 candidates were found to be associated with AIS predisposition. The ORs were observed as 0.549 (95% CI 0.3519–0.8579, P = 0.0079), 0.549 (95% CI 0.3519–0.8579, P = 0.0079), and 1.6139 (95% CI 1.0576–2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718, respectively. There was no statistical difference between main curve, severity, and genotype distributions of all of 12 SNPs. Conclusion. Genetic variants of CALM1 gene are associated with AIS susceptibility.

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“…(MMP-2 and MMP-9) seem to be decreased after exposure of disc cells to mechanical forces [35]. Regarding the role of MMPs family in idiopathic scoliosis, there are some contradictory findings in the literature about the role of gene variants of IL-6 and MMP-3 and whether MMP-3 and IL-6 promoter polymorphisms constitute important factors for the genetic predisposition to idiopathic scoliosis [36,37]. …”

Section: Discussionmentioning

confidence: 99%

Expression of matrix metalloproteinase-1 (MMP-1) in Wistar rat's intervertebral disc after experimentally induced scoliotic deformity

et al. 2011

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IntroductionA scoliotic deformity on intervertebral discs may accelerate degeneration at a molecular level with the production of metalloproteinases (MMPs). In the present experimental study we evaluated the presence of MMP-1 immunohistochemically after application of asymmetric forces in a rat intervertebral disc and the impact of the degree of the deformity on MMP-1 expression.Material-MethodThirty female Wistar rats (aged 2 months old, weighted 200 ± 10 grams) were used. All animals were age, weight and height matched. A mini Ilizarov external fixator was applied at the base of a rat tail under anaesthesia in order to create a scoliotic deformity of the intervertebral disc between the 9th and 10th vertebrae. Rats were divided into three groups according to the degree of the deformity. In group I, the deformity was 10°, in group II 30° and in group III 50°. The rats were killed 35 days after surgery. The discs were removed along with the neighbouring vertebral bodies, prepared histologically and stained immunohistochemically. Immunopositivity of disc's cells for MMP-1 was determined using a semi-quantitative scored system.ResultsMMP-1 immunopositivity was detected in disc cells of annulus fibrosus of all intervertebral disc specimens examined. The percentage of MMP-1 positive disc cells in annulus fibrosus in group I, II and III were 20%, 43% and 75%, respectively. MMP-1 positivity was significantly correlated with the degree of the deformity (p < 0,001). An increase of chondrocyte-like disc cells was observed in the outer annulus fibrosus and at the margin of the intervertebral disc adjacent to the vertebral end plates. The difference in the proportion of MMP-1 positive disc cells between the convex and the concave side was statistically not significant in group I (p = 0,6), in group II this difference was statistically significant (p < 0,01). In group III the concave side showed a remarkable reduction in the number of disc's cells and a severe degeneration of matrix microstructure.ConclusionThe present study showed that an experimentally induced scoliotic deformity on a rat tail intervertebral disc results in over-expression of MMP-1, which is dependent on the degree of the deformity and follows a dissimilar distribution between the convex and the concave side.

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Association Between IL-6 and MMP-3 Gene Polymorphisms and Adolescent Idiopathic Scoliosis

Abstract: This is the first study that has evaluated the possibility that gene variants of IL-6 and MMPs might be associated with scoliosis and suggests that MMP-3 and IL-6 promoter polymorphisms constitute important factors for the genetic predisposition to scoliosis.

Cited by 62 publications

References 15 publications

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

The Association Study of Calmodulin 1 Gene Polymorphisms with Susceptibility to Adolescent Idiopathic Scoliosis

Expression of matrix metalloproteinase-1 (MMP-1) in Wistar rat's intervertebral disc after experimentally induced scoliotic deformity

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