Journal
RHEUMATOLOGY
Volume 53, Issue 7, Pages 1291-1300Publisher
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu013
Keywords
rheumatoid arthritis; ezrin; phosphorylation; invasion; fibroblast-like synoviocytes; signal transduction
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Funding
- National Natural Science Foundation of China [81072484, 81373182]
- China Ministry of Education Foundation [20100171110058]
- Guangdong Natural Science Foundation [S2011020002358, S2013010015363]
- Guangdong Project of Science and Technology [2011B080701011, 2011B080701098]
- Guangdong Provincial Department of Education Foundation [2012KJCX0003]
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Methods. Synovial tissues were obtained from 12 patients with RA and 6 with OA, and then FLSs were separated from synovial tissues. The expression of ezrin and phosphorylated ezrin (p-ezrin) was examined by Western blotting or IF staining. A specific inhibitor of ezrin phosphorylation and small interference RNA-mediated ezrin knockdown were used to inhibit the phosphorylation of ezrin. Migration and invasion of FLSs in vitro were measured by the Boyden chamber assay. Results. Increased expression of p-ezrin protein was found in synovial tissue and FLSs in patients with RA compared with patients with OA. Stimulation with TNF-alpha and IL-1 beta increased ezrin phosphorylation in RA FLSs. Inhibition of p-ezrin protein by a specific inhibitor of phosphorylation of ezrin and small interfering RNA-mediated knockdown reduced in vitro migration and invasion, as well as actin stress fibre formation in RA FLS. Furthermore, rho kinase and p38 mitogen-activated protein kinase (MAPK) signal pathways were involved in the phosphorylation of ezrin and invasion of RA FLSs. Conclusion. Increased expression of p-ezrin may contribute to aberrant aggressive behaviours of RA FLSs, which are mediated by rho kinase and the p38 MAPK pathway. This suggests a novel strategy targeting phosphorylation of ezrin to prevent synovial invasiveness and joint destruction in RA.
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