Simvastatin prevents articular chondrocyte dedifferentiation induced by nitric oxide by inhibiting the expression of matrix metalloproteinases 1 and 13

Abstract

In this study, we investigated whether simvastatin (SVT), a statin commonly prescribed to decrease cholesterol levels, might have a therapeutic effect in OA. Primary rabbit chondrocytes were pre-treated with SVT (50 μM), then treated with sodium nitroprusside (SNP; 1 mM), a donor of nitric oxide (NO) known as a pro-inflammatory mediator, and analyzed for the expression levels of type II collagen, SOX-9, aggrecan, matrix metalloproteinases (MMPs) 1, and 13. SNP increased NO generation in a dose-dependent manner, causing a loss of type II collagen and aggrecan indicative of chondrocyte dedifferentiation, which was inhibited by SVT. SVT also reversed the increase in MMP-1 and -13 and inhibited NO production and NO synthase expression induced by SNP in articular chondrocytes. Given that MMP-1 and -13 knockdown by siRNA increased the level of type II collagen in SNP-treated cells, our results show that SVT prevented NO-induced chondrocyte damage and dedifferentiation through downregulation of MMP expression. This study showed that SVT could attenuate the degradation of articular cartilage components, which is characteristic for OA, through inhibition of MMPs in NO-treated chondrocytes, suggesting that SVT may be a novel candidate therapeutic agent for the prevention and/or treatment of OA. Impact statement: Dedifferentiation of chondrocytes is the main character of cartilage degradation. Therefore the understanding of chondrocytes dedifferentiation is essential for arthritis therapy. However, the molecular mechanism of cartilage destroy is mostly unknown. In this work we show that simvastatin (SVT) inhibits dedifferentiation by nitric oxide by blocking the expression of matrix metalloproteinases 1 and 13. These effects of SVT on dedifferentiation suggest that SVT may be used as a drug for the cure of arthritis.