Increased phosphorylation of ezrin/radixin/moesin proteins contributes to proliferation of rheumatoid fibroblast-like synoviocytes.

摘要

OBJECTIVES: Increasing evidence indicates that ezrin/radixin/moesin (ERM) proteins may play a critical role in cell proliferation. This study examined the role of ERM proteins in proliferation of fibroblast-like synoviocytes (FLS) from patients with RA. METHODS: Synovial tissues (STs) were obtained from 18 RA and 6 OA patients. The expression of ERM and its phosphorylated proteins in cultured FLS and ST was assessed by western blots or IF staining. Small interference RNA (siRNA)-mediated ERM knockdown was used to inhibit phosphorylation of ERM. Proliferation of FLS was measured by bromodeoxyuridine (BrdU) incorporation into cell DNA and by PCNA immunoblotting. RESULTS: Our study showed that increased phosphorylation of ERM proteins was found in ST and FLS from patients with RA as compared with OA patients and non-arthritis controls. Treatment with TNF-alpha, IL-1beta or PDGF-induced phosphorylation of ERM proteins in dose- and time-dependent manner by RA FLS, but did not affect the expression of total ERM protein. Rho kinase and p38MAPK signal pathways were involved in TNF-alpha-induced ERM phosphorylation. We further showed that inhibition of ERM phosphorylation by siRNA-mediated ERM knockdown suppressed TNF-alpha- or IL-1beta-induced BrdU incorporation and PCNA expression in RA FLS. CONCLUSIONS: This study provides the novel evidence that increased phosphorylation of ERM proteins may contribute to proliferation of RA FLS, suggesting that specific inhibition of ERM phosphorylation may be a new therapeutic approach for RA.