Pathogenesis Of Adolescent Idiopathic Scoliosis Research Articles

The morphological discrepancy of neuromuscular junctions between bilateral paraspinal muscles in patients with adolescent idiopathic scoliosis: A quantitative immunofluorescence assay.

Prior studies suggested that neuromuscular factors might be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS). The neuromuscular junction (NMJ) is the important pivot where the nervous system interacts with muscle fibers, but it has not been well characterized in the paraspinal muscles of AIS. This study aims to perform the quantitative morphological analysis of NMJs from paraspinal muscles of AIS. AIS patients who received surgery in our center were prospectively enrolled. Meanwhile, age-matched congenital scoliosis (CS) and non-scoliosis patients were also included as controls. Fresh samples of paraspinal muscles were harvested intraoperatively. NMJs were immunolabeled using different antibodies to reveal pre-synaptic neuronal architecture and post-synaptic motor endplates. A confocal microscope was used to acquire z-stack projections of NMJs images. Then, NMJs images were analyzed on maximum intensity projections using ImageJ software. The morphology of NMJs was quantitatively measured by a standardized 'NMJ-morph' workflow. A total of 21 variables were measured and compared between different groups. A total of 15 AIS patients, 10 CS patients and 5 normal controls were enrolled initially. For AIS group, NMJs in the convex side of paraspinal muscles demonstrated obviously decreased overlap when compared with the concave side (34.27% ± 8.09% vs. 48.11% ± 10.31%, p = 0.0036). However, no variables showed statistical difference between both sides of paraspinal muscles in CS patients. In contrast with non-scoliosis controls, both sides of paraspinal muscles in AIS patients demonstrated significantly smaller muscle bundle diameters. This study first elucidated the morphological features of NMJs from paraspinal muscles of AIS patients. The NMJs in the convex side showed smaller overlap for AIS patients, but no difference was found in CS. This proved further evidence that neuromuscular factors might contribute to the mechanisms of AIS and could be considered as a novel potential therapeutic target for the treatment of progressive AIS.

Association of IL‑6 and MMP‑3 gene polymorphisms with adolescent idiopathic scoliosis: A systematic review and meta‑analysis.

The pathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear. It has been found that interleukin-6 (IL-6) rs1800795 locus and matrix metalloproteinase-3 (MMP-3) rs3025058 locus gene polymorphisms may be associated with AIS susceptibility, which has been controversial and needs to be further confirmed by updated meta-analysis. The aim of the present study was to investigate the association of MMP-3 rs3025058 and IL-6 rs1800795 single nucleotide polymorphisms (SNPs) with susceptibility to AIS. All relevant articles that met the criteria were retrieved and included, and the publication dates were limited from January 2005 to December 2023. The allele frequencies and different genotype frequencies of IL-6 rs1800795 and MMP-3 rs3025058 loci in each study were extracted and statistically analyzed by ReviewManager 5.4 software, and the odds ratio (OR) and 95% confidence interval (95% CI) of different genetic models were calculated. The results of the meta-analysis showed that there was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS. The allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility (5A vs. 6A, OR=1.18; 95% CI, 1.04-1.33; 5A5A vs. 6A6A, OR=1.65; 95% CI, 1.23-2.21; and 5A5A vs. 5A6A + 6A6A, OR=1.54; 95% CI, 1.19-1.99). Results of subgroup analysis revealed that the allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility in the Caucasian population, and the susceptibility of AIS was associated with the genotype 5A5A of MMP-3 rs3025058 SNP in an Asian population. There was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS, while the allele 5A of MMP-3 rs3025058 locus was associated with the susceptibility to AIS, especially in the Caucasian population.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E–11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Etiopathogenesis of adolescent idiopathic scoliosis (AIS): Role of genetic and environmental factors.

Adolescent idiopathic scoliosis (AIS) has been known to be related closely to genetic factors. Higher prevalence of AIS among individuals with family history of scoliosis suggesting critical roles of genetic in the pathogenesis of AIS. However, evidence also suggested that environmental factors such as latitude and sun exposure also play a critical role in the pathogenesis of the disease. While genetic factors played an important role in the occurrence of AIS, environmental factors are more likely to affect the progression of the disease. Although the pathogenesis of AIS remains elusive, current knowledge suggests that genetic factors and its interaction with environmental factors are crucial in the development of the disease, explaining differences in clinical characteristics of AIS across the globe. The aim of this review is to summarize the current knowledge of genetic and environmental factors contributing to AIS and their interactions.

BMP6 participates in the pathogenesis of adolescent idiopathic scoliosis by regulating osteopenia.

Adolescent idiopathic scoliosis (AIS) is a complex disease characterized by three-dimensional structural deformities of the spine. Its pathogenesis is associated with osteopenia. Bone-marrow-derived mesenchymal stem cells (BMSCs) play an important role in bone metabolism. We detected 1919 differentially expressed mRNAs and 744 differentially expressed lncRNAs in BMSCs from seven patients with AIS and five patients without AIS via high-throughput sequencing. Multiple analyses identified bone morphogenetic protein-6 (BMP6) as a hub gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS. BMP6 expression was found to be decreased in AIS and its knockdown in human BMSCs significantly altered the degree of osteogenic differentiation. Additionally, CAP1-217 has been shown to be a potential upstream regulatory molecule of BMP6. We showed that CAP1-217 knockdown downregulated the expression of BMP6 and the osteogenic differentiation of BMSCs. Simultaneously, knockout of BMP6 in zebrafish embryos significantly increased the deformity rate. The findings of this study suggest that BMP6 is a key gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS via the CAP1-217/BMP6/RUNX2 axis.

Adolescent idiopathic scoliosis is associated with muscle area asymmetries in the lumbar spine.

While the etiopathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear, it is assumed that muscular asymmetries contribute to curve progression. As previous studies have found asymmetries of the thoracic paraspinal muscles in AIS patients, our study's aim was to analyze differences in the erector spinae, multifidus, quadratus lumborum, and psoas muscles of the lumbar spine depending on the curve's radiographic characteristics. We retrospectively included all patients who received posterior reposition spondylodesis for AIS treatment at our institution. Patients were classified according to the Lenke classification. Muscle cross-sectional areas were obtained from magnetic resonance imaging of the lumbar spine. Data were analyzed with the Wilcoxon rank sum test, the Kruskal-Wallis test with post hoc testing, or the Spearman's correlation coefficient. Seventy-four (14 males and 60 females) AIS patients with a median age of 16 (IQR ± 4) years and a mean Cobb angle of 56.0° (± 18.0°) were included. In curve types Lenke 1 and 2 (n = 45), the erector spinae (p < 0.001) and multifidus (p < 0.001) muscles had a significantly larger cross-sectional area on the convex side, whereas the quadratus lumborum (p = 0.034) and psoas (p < 0.001) muscles each had a significantly larger cross-sectional area on the lumbar contralateral side. Our results show an asymmetry of the lumbar spine's muscles which depends on both the convexity and the extent of the scoliotic curve. While our results cannot prove whether these differences are the deformity's cause or effect, they may contribute to a better understanding of AIS pathogenesis and may allow for more specific preoperative physiotherapy.

Research progress on the regulation of bone marrow stem cells by noncoding RNAs in adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity in young women, but its pathogenesis remains unclear. The primary pathogenic factors contributing to its development include genetics, abnormal bone metabolism, and endocrine factors. Bone marrow stem cells (BMSCs) play a crucial role in the pathogenesis of AIS by regulating its occurrence and progression. Noncoding RNAs (ncRNAs) are also involved in the pathogenesis of AIS, and their role in regulating BMSCs in patients with AIS requires further evaluation. In this review, we discuss the relevant literature regarding the osteogenic, chondrogenic, and lipogenic differentiation of BMSCs. The corresponding mechanisms of ncRNA-mediated BMSC regulation in patients with AIS, recent advancements in AIS and ncRNA research, and the importance of ncRNA translation profiling and multiomics are highlighted.

Association between lean mass and adolescent idiopathic scoliosis: a meta-analysis

ObjectiveThe objective of this meta-analysis was to evaluate the association between lean mass and adolescent idiopathic scoliosis (AIS).MethodsEnglish databases CENTRAL (The Cochrane Library and the Cochrane Back Review Group Trials Register), MEDLINE, EMBASE, PubMed, Web of Science and Chinese databases CBM, CNKI, VIP, WANGFANG DATA were searched for the relevant case control studies and cross-sectional studies. Two authors selected studies and extracted data independently. Data analysis was performed by Stata15.0.ResultsEight studies were included, with a total of 1771 cases of AIS and 6340 controls. AIS group had a lower lean mass compared to control group [MD = − 1.95, 95% CI (− 2.96, − 0.93)]. In the subgroup analysis, female AIS patients had a lower lean mass than the control group [MD = − 1.76, 95% CI (− 2.63, − 0.88)]. The mean difference of lean mass between AIS patients and control group in studies with adults [MD = − 3.96, 95% CI (− 7.26, − 0.67)] is much greater than studies without adults [MD = − 1.04, 95% CI (− 1.59, − 0.49)]. There was not statistically significant in European studies [MD = − 2.10, 95% CI (− 4.35, 0.14)], but in Asian studies lean mass in AIS patients was lower than the control group [MD = − 2.26, 95% CI (− 3.98, − 0.54)]. Study type, gender, age, and geography condition were thought to have no effect on the primary outcome of lean mass by subgroup analysis.ConclusionIn the meta-analysis, AIS group had a lower lean mass compared to control group, which indicated that lean mass may be involved in the pathogenesis of AIS. But limited by the number of studies we included; the above conclusions need to be validated by more high-quality studies.

Quantifying Muscle Size Asymmetry in Adolescent Idiopathic Scoliosis Using Three-dimensional Magnetic Resonance Imaging.

This is a case-control study of prospectively collected data. To quantify paraspinal muscle size asymmetry in adolescent idiopathic scoliosis (AIS) and determine if this asymmetry is (i) greater than observed in adolescent controls with symmetrical spines; and (ii) positively associated with skeletal maturity using Risser grade, scoliosis severity using the Cobb angle, and chronological age in years. AIS is a three-dimensional deformity of the spine which occurs in 2.5% to 3.7% of the Australian population. There is some evidence of asymmetry in paraspinal muscle activation and morphology in AIS. Asymmetric paraspinal muscle forces may facilitate asymmetric vertebral growth during adolescence. An asymmetry index [Ln(concave/convex volume)] of deep and superficial paraspinal muscle volumes, at the level of the major curve apex (Thoracic 8-9 th vertebral level) and lower-end vertebrae ( LEV , Thoracic 10-12 th vertebral level), was determined from three-dimensional Magnetic Resonance Imaging of 25 adolescents with AIS (all right thoracic curves), and 22 healthy controls (convex=left); all female, 10 to 16 years. Asymmetry index of deep paraspinal muscle volumes was greater in AIS (0.16±0.20) than healthy spine controls (-0.06±0.13) at the level of the apex ( P <0.01, linear mixed-effects analysis) but not LEV ( P >0.05). Asymmetry index was positively correlated with Risser grade ( r =0.50, P <0.05) and scoliosis Cobb angle ( r =0.45, P <0.05), but not age ( r =0.34, P >0.05). There was no difference in the asymmetry index of superficial paraspinal muscle volumes between AIS and controls ( P >0.05). The asymmetry of deep apical paraspinal muscle volume in AIS at the scoliosis apex is greater than that observed at equivalent vertebral levels in controls and may play a role in the pathogenesis of AIS.

The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis

Adolescent Idiopathic Scoliosis (AIS) is a common pediatric skeletal disease highly occurred in females. The pathogenesis of AIS has not been fully elucidated. Here, we reveal that ESR1 (Estrogen Receptor 1) expression declines in muscle stem/progenitor cells at the concave side of AIS patients. Furthermore, ESR1 is required for muscle stem/progenitor cell differentiation and disrupted ESR1 signaling leads to differentiation defects. The imbalance of ESR1 signaling in the para-spinal muscles induces scoliosis in mice, while reactivation of ESR1 signaling at the concave side by an FDA approved drug Raloxifene alleviates the curve progression. This work reveals that the asymmetric inactivation of ESR1 signaling is one of the causes of AIS. Reactivation of ESR1 signaling in para-spinal muscle by Raloxifene at the concave side could be a new strategy to treat AIS.

Slow twitch paraspinal muscle dysregulation in adolescent idiopathic scoliosis exhibiting HIF-2α misexpression.

Adolescent idiopathic scoliosis (AIS) refers to a three-dimensional spinal deformity which has a typical onset during adolescence. In most cases, the cause of the deformity cannot be clearly identified. Unbalanced paraspinal muscle activity in AIS patients was reported and hypoxia was implicated to regulate myogenesis. This study aims to investigate the association between myogenesis/muscle toning and HIF-αs activity in the pathogenesis of AIS. HIF-αs expression was examined by enzyme-linked immunosorbent assay and western blot in paraspinal myoblasts isolated from 18 subjects who underwent deformity correction surgery. QPCR was conducted to measure the gene expression levels of perinatal muscle fiber markers MYH3, MYH8; slow twitch muscle fiber markers MHY7; fast twitch muscle fiber markers MYH4; and myogenic regulatory factors MYF5 and MYOG. Slow and fast twitch muscle fiber composition in concave/convex paraspinal musculature of AIS subjects was evaluated by immunostaining of myosin heavy chain type I (MyHC I) and myosin heavy chain type II (MyHC II). Reduced HIF-2α induction under hypoxia was found in paraspinal myoblast culture of 33% AIS subjects. We detected a suppression of perinatal and slow twitch muscle fiber associated genes, but not fast twitch muscle fiber-associated genes and myogenic regulatory factors in HIF-2α misexpressed AIS myoblasts. Distinct reduction of slow twitch muscle fiber was evidenced in convex paraspinal musculature, suggesting an asymmetric expression of slow twitch muscle fiber in HIF-2α misexpressed AIS patients. This study indicates an association of abnormal HIF-2α expression in paraspinal myoblasts and a disproportionate slow twitch muscle fiber content in the convexity of the curvature in a subset of AIS subjects, suggesting HIF-2α dysregulation as a possible risk factor for AIS. The role of HIF-2α in paraspinal muscle function during spinal growth and its relevance in AIS prognosis warrants further investigation.

A Genetic Variant of the ROBO3 Gene is Associated With Adolescent Idiopathic Scoliosis in the Chinese Population.

A case-control association study. This study aimed to reveal whether mutations within roundabout receptor 3 ( ROBO3 ) gene were related to adolescent idiopathic scoliosis (AIS) in Chinese Han population and to investigate the functional role of ROBO3 in the pathogenesis and progression of AIS. ROBO3 is essential for the regulation of hindbrain axonal cell migration and midline crossing. Studies have demonstrated that ROBO3 homozygous mutations are associated with horizontal gaze palsy with progressive scoliosis. However, whether and how ROBO3 contributed to the development of scoliosis remains unclear. Whole exome sequencing was performed in 135 AIS patients and 267 healthy controls to evaluate the differences of single nucleotide polymorphism variants within ROBO3 . Then the identified variant of ROBO3 was genotyped in another cohort included 1140 AIS patients and 1580 controls. Moreover, paraspinal muscles were collected from 39 AIS patients and 45 lumbar disk herniation patients for the measurement of ROBO3 mRNA expression. The χ 2 test, Fisher exact test or the Student t test were used to compare intergroup data. Pearson correlation was used to determine the association between ROBO3 expression and clinical phenotypes. A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS through exome sequencing. The genotyping cohort demonstrated a higher frequency of allele A in AIS patients compared to controls (7.89% vs . 4.30%, P <0.001, odds ratio=1.87). In addition, the expression of ROBO3 in paraspinal muscles was inversely correlated with the Cobb angle ( P =0.043, r2 =0.1059). A significant association was identified between the gene variant (rs74787566) of ROBO3 and the development of AIS. The reduced expression of ROBO3 could result in the progression of curve magnitude in patients with AIS. Further studies are needed to verify the functional role of ROBO3 in the development of AIS. Level III.

Association of Ligamentum Flavum Hypertrophy with Adolescent Idiopathic Scoliosis Progression-Comparative Microarray Gene Expression Analysis.

The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides of the apex of the curvature in 22 patients with AIS. Next, gene expression was compared among neutral vertebral LF and LF on the convex and concave sides of the apex of the curvature in patients with AIS. Histological and microarray analyses of the LF were compared among neutral vertebrae (control) and the LF on the apex of the curvatures. The mean area of LF in the without scoliosis, apical concave, and convex with scoliosis groups was 10.5, 13.5, and 20.3 mm2, respectively. There were significant differences among the three groups (p < 0.05). Histological analysis showed that the ratio of fibers (Collagen/Elastic) was significantly increased on the convex side compared to the concave side (p < 0.05). Microarray analysis showed that ERC2 and MAFB showed significantly increased gene expression on the convex side compared with those of the concave side and the neutral vertebral LF cells. These genes were significantly associated with increased expression of collagen by LF cells (p < 0.05). LF hypertrophy was identified in scoliosis patients, and the convex side was significantly more hypertrophic than that of the concave side. ERC2 and MAFB genes were associated with LF hypertrophy in patients with AIS. These phenomena are likely to be associated with the progression of scoliosis.

Tent5a modulates muscle fiber formation in adolescent idiopathic scoliosis via maintenance of myogenin expression.

ObjectiveParavertebral muscle asymmetry may be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS), and the Tent5a protein was recently identified as a novel active noncanonical poly(A) polymerase. We, therefore, explored the function of the AIS susceptibility gene Tent5a in myoblasts.Materials and methodsRNA‐seq of AIS paravertebral muscle was performed, and the molecular differences in paravertebral muscle were investigated. Twenty‐four AIS susceptibility genes were screened, and differential expression of Tent5a in paravertebral muscles was confirmed with qPCR and Western blot. After the knockdown of Tent5a, the functional effects of Tent5a on C2C12 cell proliferation, migration, and apoptosis were detected by Cell Counting Kit‐8 assay, wound‐healing assay, and TUNEL assay, respectively. Myogenic differentiation markers were tested with immunofluorescence and qPCR in vitro, and muscle fiber formation was compared in vivo.ResultsThe AIS susceptibility gene Tent5a was differentially expressed in AIS paravertebral muscles. Tent5a knockdown inhibited the proliferation and migration of C2C12 cells and inhibited the maturation of type I muscle fibers in vitro and in vivo. Mechanistically, the expression of myogenin was decreased along with the suppression of Tent5a.Conclusions Tent5a plays an important role in the proliferation and migration of myoblasts, and it regulates muscle fiber maturation by maintaining the stability of myogenin. Tent5a may be involved in the pathogenesis of AIS by regulating the formation of muscle fiber type I.

The role of endocrine hormones in the pathogenesis of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity characterized by changes in the three-dimensional structure of the spine. It usually initiates during puberty, the peak period of human growth when the secretion of numerous hormones is changing, and it is more common in females than in males. Accumulating evidence shows that the abnormal levels of many hormones including estrogen, melatonin, growth hormone, leptin, adiponectin and ghrelin, may be related to the occurrence and development of AIS. The purpose of this review is to provide a summary and critique of the research published on each hormone over the past 20years, and to highlight areas for future study. It is hoped that the presentation will help provide a better understanding of the role of endocrine hormones in the pathogenesis of AIS.

A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait-A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis.

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development.

The uncoupled anterior and posterior spinal ligament tension (UAPLT) – An improvement to three-dimensional spring model of adolescent idiopathic scoliosis (AIS) pathogenesis

The pathogenesis of Adolescent Idiopathic Scoliosis (AIS) remains unclear. Previous research proposed that ligament laxity is a clinical feature that can be easily overlooked in patients with AIS. We speculated a new hypothesis which is an improvement of our three-dimensional spring model hypothesis of AIS pathogenesis. The tethered string in the spring model stimulates the spinal ligament instead of spinal cord. Spinal overgrowth in the adolescent age leads to higher tension of posterior spinal ligament. And the ligament laxity leads to lower tension of anterior spinal ligament. This uncoupled anterior and posterior spinal ligament tension maybe the key cause of AIS.

Nontargeted Metabolomic Analysis of Plasma Metabolite Changes in Patients with Adolescent Idiopathic Scoliosis.

Objective Adolescent idiopathic scoliosis (AIS) is a relatively common spinal rotation deformity, and the pathogenesis of AIS is accompanied by metabolic dysfunction and changes in biochemical factors. In this study, plasma metabolite changes in AIS patients were analyzed based on nontargeted metabolomics to provide new insights for clarifying functional metabolic abnormalities in AIS patients. Methods Clinical indexes and blood samples were collected from 12 healthy subjects and 16 AIS patients. Metabolomics was used to analyze the changes in metabolites in plasma samples. The correlation between plasma metabolites and clinical indexes was analyzed by the Spearman rank correlation coefficient. Results Analysis of clinical data showed that the body weight, body mass index (BMI), and bone mineral density (BMD) index of the AIS group significantly decreased, while the blood phosphorus and Cobb angles increased significantly. Metabolomic analysis showed significant changes in 72 differential metabolites in the plasma of the AIS group, mainly including organooxygen compounds, carboxylic acids and derivatives, fatty acyls, steroids and steroid derivatives, and keto acids and derivatives. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed that arginine biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, and citrate cycle (TCA cycle) were significantly enriched in the AIS and healthy groups. Spearman rank correlation coefficient analysis showed that the plasma metabolites C00026 (oxoglutarate), C00062 (L-arginine, arginine), C01042 (N-acetylaspartate), and C00158 (citrate) were significantly correlated with clinical indexes in AIS patients. In the healthy group, the plasma metabolites C00122 (fumarate), C00025 (glutamate and L-glutamic acid) and C00149 (malate, L-malic acid) were significantly correlated with clinical indexes, while C00624 (N-acetylglutamate) was not significantly correlated with the clinical indexes. Conclusion The occurrence of AIS led to changes in clinical indexes and plasma metabolites. Plasma biomarkers and functional metabolic pathways were correlated with clinical indexes, which might provide new insights for the diagnosis and treatment of AIS.

Lower androgen levels promote abnormal cartilage development in female patients with adolescent idiopathic scoliosis

BackgroundAdolescent idiopathic scoliosis (AIS) is a disease characterized by changes in the three-dimensional structure of the spine. Studies have shown that the development of AIS might be associated with genetic, biomechanics, endocrine factors and abnormal bone or cartilage development.MethodsBlood samples collected from 301 female patients (161 females with AIS and 140 females without AIS) were used for genotyping. Forty-eight serum samples from 161 females with AIS and 40 serum samples from 140 females without AIS were subjected to enzyme-linked immunosorbent assays (ELISAs). We also evaluated 32 facet joints (18 females with AIS and 14 females without AIS from the 301 female patients) using immunohistochemistry, Western blotting, and isolation of human primary chondrocytes, among other methods. We treated the AIS primary chondrocytes with dihydrotestosterone (DHT) to verify the relationship among androgen, the androgen receptor (AR), and its downstream pathway proteins.ResultsThe serum androgen level in the AIS group was significantly decreased (1.94±0.09 vs. 2.284±0.103) compared with that in the non-AIS (control) group. The single nucleotide polymorphism genotyping results showed that the mutation rates of rs6259 between the AIS and control groups were significantly different (G/G genotype: 48.4% vs. 42.1%, G/A genotype: 40.4% vs. 35.7%, P<0.05). The levels of interleukin (IL)-6 and metalloproteinase (MMP)-13 were increased in the cartilage of AIS patients, and these patients also exhibited decreased AR levels. The cell experiment results showed that androgen reduced the degree of abnormal cartilage development in female AIS patients through the AR/IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway.ConclusionsOur study provides a new perspective on the pathogenesis of AIS and indicates that decreased androgen levels in female AIS patients play a potential role in the development of AIS via the AR/IL-6/STAT3 signaling pathway.