A critical role of Cyr61 in interleukin‐17–dependent proliferation of fibroblast‐like synoviocytes in rheumatoid arthritis

Abstract

Objective: Fibroblast‐like synoviocytes (FLS) are a major component of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Cyr61 (CCN1) is a product of a growth factor–inducible immediate early gene and is involved in cell adhesion, proliferation, and differentiation. However, the role that Cyr61 plays in FLS proliferation has remained undetermined. The aim of this study was to identify the role of Cyr61 in regulating the proliferation of FLS derived from patients with RA. Methods: Expression of Cyr61 in synovial tissue (ST) and in FLS was determined simultaneously using immunohistochemistry, real‐time polymerase chain reaction, and Western blotting. Cyr61 levels in synovial fluid (SF) were determined by enzyme‐linked immunosorbent assay. FLS proliferation stimulated by SF, Cyr61, and interleukin‐17 (IL‐17) was measured by thymidine incorporation. Activation of signal transduction pathways was determined by Western blotting and confocal microscopy. Results: Cyr61 was overexpressed in ST, FLS, and SF samples from RA patients as compared with samples from normal controls. Elevated levels of Cyr61 in RA SF promoted the proliferation of FLS, an effect that was abrogated by a neutralizing monoclonal antibody against human Cyr61. Furthermore, in samples from RA patients, Cyr61 was found to protect FLS from apoptosis and to sustain the expression of Bcl‐2 in FLS. Most importantly, the expression of Cyr61 in FLS was regulated by IL‐17 mainly via the p38 MAPK and NF‐κB signaling pathways. Knockdown of expression of the Cyr61 gene inhibited IL‐17–stimulated FLS proliferation. Conclusion: Our findings indicate that Cyr61 plays a critical role in IL‐17–mediated proliferation of FLS in RA and likely contributes to hyperplasia of synovial lining cells and eventually to joint destruction in patients with RA.