Forkhead box C1 promotes the pathology of osteoarthritis by upregulating β‐catenin in synovial fibroblasts

Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration, and no effective treatment is available. The OA classification has shifted from a cartilage-only disease to a whole-joint disease, and the synovial membrane plays an important role. Therefore, studies are needed to identify additional genes that regulate the pathological changes in the synovial membrane to develop a promising therapeutic strategy for OA. Here, we validated that the expression of forkhead box protein C1 (FoxC1) and beta-catenin was upregulated in OA synovial membranes and synovial fibroblasts (SFs). Gain- and loss-of-function studies revealed that FoxC1 overexpression promoted, whilst silencing inhibited OA synovial fibroblast (OASF) proliferation and pro-inflammatory cytokine [interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha)] production. FoxC1 overexpression increased beta-catenin mRNA, total and nuclear protein expression in OASFs and upregulated a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), fibronectin, matrix metalloproteinase 3 (MMP3) and matrix metalloproteinase 13 (MMP13) mRNA and total protein expression in OASFs. Conversely, FoxC1 knockdown reduced beta-catenin mRNA, total and nuclear protein expression in OASFs and reduced ADAMTS-5, fibronectin, MMP3 and MMP13 mRNA and total protein expression in OASFs. beta-catenin mediates FoxC1-induced pathological changes (proliferation, catabolic regulation and inflammation) in OASFs. MicroRNA-200a-3p (miR-200a-3p) binds to the 3'-UTR of FoxC1 and mediates FoxC1 expression. Intra-articular FoxC1-specific siRNA transfection hindered OA development in mice. Therefore, our results demonstrate the key role FoxC1 plays in vivo and in vitro in OA synovial pathology, possibly identifying a potential novel therapeutic target for OA.