Elucidation of the Mechanism by Which a ADAMTS5 Gene MicroRNA-Binding Site Single Nucleotide Polymorphism Affects the...

The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) within the 3' untranslated region of the microRNA (miRNA)-binding site of the ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) gene and the risk of knee osteoarthritis (KOA) and its mechanism. Sanger sequencing was used to determine the genotypes of three ADAMTS5 gene SNPs (rs3171407, rs229071, and rs229077) from 310 patients suffering from osteoarthritis of the knee joint (KOA) and 310 healthy controls. The levels of the miRNAs, thsa-miR-103b, hsa-miR-144-3p, and hsa-miR-105-5p in plasma, and the level of ADAMTS5 mRNA in the articular cartilage of 132 patients with KOA were detected by real-time quantitative PCR. The G allele at the rs3171407 locus of the ADAMTS5 gene was demonstrated to be a protective genetic factor for KOA. In addition, the risk of developing KOA was significantly increased in subjects carrying the C allele at the rs229071 locus. The risk of developing KOA in carriers of the G allele at locus rs229077 was 1.49 times greater than those with the A allele. The level of the hsa-miR-144-3p was increased, and the expression level of the ADAMTS5 protein was decreased in carriers of the T allele at the rs229071 locus. In carriers of rs229077 locus A allele the hsa-miR-105-5p level was increased and the expression level of ADAMTS5 protein was decreased. SNPs at the rs3171407, rs229071, and rs229077 loci of the ADAMTS5 gene are related to the risk of OA. The likely mechanism underlying these observations is that these SNPs affect the regulation of ADAMTS5 protein expression through miRNAs; however, this needs to be verified using in vivo models.