Genetics/genomics in osteoarthritis

Abstract

In this year review recent developments in genetics/genomics of osteoarthritis (OA) are discussed to improve our understanding of OA pathophysiology. In OA genetics, a meta-analysis of genome wide association studies (GWAS) revealed novel loci for hip OA, among which a variant near the NCOA3 (nuclear receptor coactivator 3) gene and an 199-candidate gene meta-analysis of GWAS demonstrated association only between COL11A1 and VEGF genes and hip OA. In addition, the effect of the FTO variant on OA risk was found to be mediated through body mass index. In OA genomics, four trans-acting factors were identified that bind to GDF5 and regulate its expression via the OA susceptibility locus rs143383. Gene expression microarray studies in OA synovium showed elevation of collagens and cross-linking enzymes (COL1A1, COL5A1, PLOD2, LOX and TIMP1) responsive to TGF-β and also differential expression pattern between different areas of the osteoarthritic synovial membrane. Microarray analysis in peripheral blood demonstrated differentially expressed genes involved in apoptotic pathways between OA patients and healthy controls. Furthermore, gene expression profiling in OA subchondral bone revealed differentially expressed genes involved in cartilage and bone development and OA pathogenesis. In epigenetics, a number of studies identified the role of several microRNAs (miRs) in regulation of gene expression in chondrocytes and highlighted their use as potential drug targets. Among them, miR-125 was implicated in ADAMTS-4 regulation, miR-127b in MMP-13 regulation and IL-1β induced catabolic effects, miR-1247 was shown to directly target SOX9 and overexpression of hsa-miR-148a in OA chondrocytes inhibited hypertrophic differentiation and increased COL2A1 production. Future studies must focus on the integration of genetics and genomics for the identification of signaling pathways and regulatory networks responsible for OA development.