Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS.
Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2-3% of school-age children worldwide(1). Genetic factors have been implicated in its etiology(2). Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10(-19); odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.
BackgroundThe current surgical procedure of choice for lumbar intervertebral disc (IVD) herniation is discectomy. However, defects within IVD produced upon discectomy may impair tissue healing and predispose patients to subsequent IVD degeneration. This study aimed to investigate whether the use of an acellular bioresorbable ultra-purified alginate (UPAL) gel implantation system is safe and effective as a reparative therapeutic strategy after lumbar discectomy.MethodsHuman IVD cells were cultured in a three-dimensional system in UPAL gel. In addition, lumbar spines of sheep were used for mechanical analysis. Finally, the gel was implanted into IVD after discectomy in rabbits and sheep in vivo.FindingsThe UPAL gel was biocompatible with human IVD cells and promoted extracellular matrix production after discectomy, demonstrating sufficient biomechanical characteristics without material protrusion.InterpretationThe present results indicate the safety and efficacy of UPAL gels in a large animal model and suggest that these gels represent a novel therapeutic strategy after discectomy in cases of lumbar IVD herniation.FundGrant-in-Aid for the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.
Objective. Although the etiology of intervertebral disc degeneration is poorly understood, one possible approach for its regulation is apoptosis inhibition. This study was undertaken to investigate the antiapoptotic effects of caspase 3 in intervertebral disc degeneration in rabbits.Methods. We investigated the effects of caspase 3 small interfering RNA (siRNA) on rabbit nucleus pulposus cells in a serum-starved medium. The effects of direct injection of Alexa Fluor 555-labeled caspase 3 siRNA into the intervertebral disc were also determined in vivo using the rabbit anular needle puncture model.Results. Rabbit nucleus pulposus cells transfected with caspase 3 siRNA showed a significant decrease in serum-starved apoptotic cells. After local injection of caspase 3 siRNA into intervertebral discs, red fluorescence was observed in the nucleus pulposus upon treatment with Alexa Fluor 555-labeled caspase 3 siRNA. Caspase 3 messenger RNA and protein were down-regulated in the caspase 3 siRNA group. Magnetic resonance imaging and histologic evaluation showed that degenerative changes were significantly suppressed in the caspase 3 siRNA group 4 and 8 weeks after injection. Quantification of TUNEL staining showed that the caspase 3 siRNA group had significantly fewer apoptotic nucleus pulposus cells than the control siRNA group.Conclusion. Our findings indicate that caspase 3 knockdown in rabbit intervertebral disc cells is effective in preventing apoptotic cell death, thus regulating intervertebral disc degeneration.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.
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