Inhibition of transient receptor potential canonical 6 attenuates fibroblast-like synoviocytes mediated synovial inflammation and joint destruction in rheumatoid arthritis.

Abstract

We aimed to define the importance of transient receptor potential canonical 6 (TRPC6) expression and function in fibroblast-like synoviocytes (FLSs) and to investigate the contribution of TRPC6 in the model of rheumatoid arthritis (RA). We compared TRPC6 expression levels in FLSs from RA patients (RA-FLSs), and in FLSs from osteoarthritis (OA) patients (OA-FLSs). By using vitro functional assays which united with small interfering RNA-induced knockdown and functional modulation of TRPC6 in RA-FLSs. Finally, we confirmed the effectiveness of regulating TRPC6 in a collagen induced arthritis (CIA) mice model. We found that FLSs expressed the TRPC6 as their major Transient receptor potential canonical channel. Both mRNA and protein expression of TRPC6 were found somewhat higher levels in RA-FLSs than in OA-FLSs. Moreover, inhibiting expression of TRPC6 in vitro reduced proliferation of, as well as inflammatory mediator and protease production by, RA-FLSs, whereas opening native TRPC6 enhanced both proliferation and inflammatory mediator of RA-FLSs. Additionally, a TRPC6 deficiency in mice blunted the development of experimental RA, CIA models, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation. Our results demonstrated a critical role of TRPC6 in regulating FLSs mediated inflammation. Therefore, TRPC6 represents potential therapeutic targets in RA.