Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease stimulated by inflammatory mediators and oxygen species within joint space cause joint deformity and destruction. Excess amounts of Cysteine-rich protein 61 (Cyr61) will stimulate dysregulated angiogenesis, macrophage chemotaxis and cell apoptosis. Epidemiological study also suggested the connection between Cyr61 and RA development, although the pathogenesis remained unclear. In patients with autoimmune disease, genetic polymorphism was noted in their forkhead transcription factor (FoxO), a molecule responsible for DNA repair and longevity. Furthermore, a positive correlation between the degree of genetic deformity and disease severity was demonstrated. Sirtuin (SIRT) -1 is an essential co-factor of FoxO activity: interaction between SIRT1 and FoxO can resist the ROS-induced apoptosis. Concerning the connection between FoxO and RA, only a few studies have addressed the modulation of FoxO on the apoptosis of fibroblast-like synoviocyte, macrophages and T cells in RA. However, great controversy about the role of FoxO on their fate still existed. Taken together, it may be possible that FoxO may involve in RA development via its inflammation-modulating effect. Statin can attenuate inflammation, in addition to its well-known cholesterol-lowering effect. Mechanisms underlying the modulation of statin on RA progression are still unclear, since most of the investigations on the effects of statin on RA were epidemiological studies. The aims of the study were to examine the role of SIRT1/FoxO3a in Cyr61 expression in rheumatoid arthritis synovial fibroblasts (RASFs) and the influence of simvastatin on this pathway. In a model of collagen-induced arthritis (CIA), the relation between disease progression and FoxO3a/Cyr61 signaling in synovial fibroblasts (SFs) was assessed

Methods: Cyr61 and SIRT1 expressions, localization of FoxO3a in the nucleus/cytoplasm and phosphorylation/acetylation of FoxO3a were examined by immuneprecipitation and Western blotting. Promoter activity of Cyr61 gene was evaluated by luciferase assay with or without forced expression of FoxO3a and SIRT1 by lentiviral transduction. FoxO3a/Cyr61 promoter interaction was examined by chromatin immunoprecipitation. In CIA rats, expressions of Cyr61 and phospho-FoxO3a in SFs were examined by immunohistochemistry.

Results: In RASFs, simvastatin suppressed Cyr61 and CCL20 secretion. Simvastatin maintained Foxo3a binding to Cyr61promoter. SIRT1 decreased Cyr61 expression and deacetylated FoxO3a whereas simvastatin upregulated SIRT1 and SIRT1/FoxO3a binding in RASFs. In rats with CIA, simvastatin alleviated arthritis and suppressed Cyr61 expression and FoxO3a phosphorylation in SFs.

Conclusion: Cyr61 is important in RA pathogenesis and SIRT1/FoxO3a signaling is crucial to Cyr61 induction in RASFs. Simvastatin is beneficial to inflammatory arthritis by upregulating SIRT1/FoxO3a signaling in SFs. Continued study of the pathways linking sirtuins, FoxO proteins and inflammatory responses of RASFs may provide new insights into the pathophysiology of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/statin-alleviates-rheumatoid-arthritis-progression-through-diminishing-inflammation-or-oxidative-stress-induced-cyr61-synthesis/