ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca2+/Rac1 pathway

Abstract Acid-sensitive ion channels (ASICs) as Ca2+ and Na+ cation channels are activated by changing in extracellular pH, which expressed in various diseases and participated in underlying pathogenesis. ASIC1a is involved in migration and invasion of various tumor cells. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) located at the edge of the synovium were identified as key players in the pathophysiological process of rheumatoid arthritis and reported to have many similar properties to tumor cells. Here, we investigated the roles of ASIC1a in synovial invasion in vivo and the migration and invasion of RA-FLSs in vitro. Our results showed ASIC1a highly expressed in RA synovial tissues and RA-FLSs. Inhibition of ASIC1a by PCTX-1 reduces synovial invasion and the expressions of MMP2, MMP9, p-FAK to protect articular cartilage in AA rats. Moreover, the acidity-promoted invasion and migration as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were down-regulated by ASIC1a-RNAi and PCTX-1 while they were increased by overexpression-ASIC1a. ASIC1a mediated Ca2+ influx and the activation of Ras-related C3 botulinum toxin substrate 1(Rac1), which was decreased by the intracellular calcium chelating agent BAPTA-AM. Meanwhile, the migration and invasion as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were decreased by Rac1 specific blocker NSC23766. In conclusion, this study indicated that ASIC1a may be a master regulator of synovial invasion via Ca2+/Rac1 pathway.