Statin attenuates osteoblastic cell Cyr61 expression via modulating Sirtuin/FoxO3a/Cyr61 signaling pathway: a therapeutic potential for arthritis.

Rheumatoid arthritis is chronic, inflammatory, systemic, autoimmune diseases characterized by chronic arthritis leading to progressive joint erosions. Inflammation recruits immune cells such as macrophage to the site leading to bone erosion. The recruitment of inflammatory cell is the major risk factor in the arthritis and the mechanism is needed more research. Cyr61, the CCN family, named CCN1 has been reported plays an important role in RA patients. Cyr61 mRNA has a significant increase in RA patients and promotes macrophage migration. In our collagen-induced arthritis(CIA) model, Cyr61 expressed and seems to recruit macrophage to bone resorption area means that it may promote macrophage infiltration and resulted in CIA progression. In vitro, treatment of Cyr61 recombinant protein direct promoted macrophage migration and enhanced CCL2 chemokine expression in U2OS. Thus, Cyr61 has the ability to deteriorate RA progression.tatin, a cholesterol synthesis inhibitor, has been reported to have a potential in therapy of arthritis. To investigate the effect of arthritis, we administrated simvastatin to joint space and led to alleviate CIA progression. By local injection of simvastain, this way of administration can avoid the liver-specific characteristic. In U2OS cell, treatment of simvastatin decreased Cyr61 expression via activation FoxO3a. Simvastatin activated FoxO3a through promoting its nuclear translocation. FoxO3a activity is mediated by post-transcriptional modification that includes phosphorylation and acetylation. Phosphorylation at Thr32, Ser253 and Ser315 leads to nucleus export and acetylation attenuates FoxO3a DNA binding affinity. Simvastain activated FoxO3a through decreasing its phosphorylation and acetylation. Thus, nuclear FoxO3a bound to Cyr61 promoter and repressed transcription. Deacetylation of FoxO3a seems to SIRT1-dependent manner. Treatment of Simvastatin enhanced SIRT1 activity and promoted FoxO3a interaction. The references related to statins on FoxO3a phosphorylation are much clear than acetylation. We found a way that statins mediate FoxO3a acetylation n summary, simvastatin represses Cyr61 expression through promoting FoxO3a deacetylation and nucleus translocation in vitro. In animal model, simvstatin alleviates CIA progression, decreases Cyr61 expression and promotes FoxO3a nuclear translocation that correlated with in vitro data. By confirming the SIRT1/FoxO3a/Cyr61 pathway, it will be a potential target in therapy of RA.