PPARγ Agonist Rosiglitazone Inhibits Migration and Invasion by Downregulating Cyr61 in Rheumatoid Arthritis Fibroblast‐like Synoviocytes

Aim: Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists have anti-inflammatory properties that reduce inflammatory cytokine production in rheumatoid arthritis (RA). Cysteine-rich angiogenic inducer 61 (Cyr61) is associated with diseases related to chronic inflammation. The aim of this study was to investigate the mechanisms underlying the effects of PPAR gamma agonists on tumor necrosis factor (TNF)-alpha-induced fibroblast-like synoviocyte (FLS) invasion and migration, as well as Cyr61 production, in RA-FLS. Methods: FLS were cultured with TNF-alpha and Cyr61 in the presence or absence of PPAR gamma agonists. Matrix metalloproteinase and Cyr61 expression levels in RA-FLS and culture supernatants were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The migration and invasion phenotypes of RA-FLS were determined by wound healing and Boyden chamber assays. Results: Cyr61 protein was expressed in RA-FLS, and its intracellular expression and secretion levels were increased by TNF-alpha. Moreover, Cyr61 directly promoted RA-FLS migration and invasion. Rosiglitazone (RSG) significantly decreased TNF-alpha-induced Cyr61 expression. RSG decreased TNF-alpha-induced nuclear factor (NF)-kappa B activation and inhibitor of kappa B alpha degradation. Furthermore, RSG inhibited TNF-alpha-induced RA-FLS migration and invasion and decreased Cyr61 treatment-induced RA-FLS invasion. Finally, blocking Cyr61 significantly attenuated TNF-alpha-induced migration. Conclusions: Our results demonstrate for the first time that PPAR gamma agonists may have beneficial effects on the migration and invasion of RA-FLS via the downregulation of Cyr61. Therefore, PPAR gamma agonists could be potential treatment targets for RA.