miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively.

Abstract

The aim of this study was to determine the mechanism underlying the association between one-carbon metabolism and DNA methylation during chronic degenerative joint disorder, osteoarthritis (OA). Articular chondrocytes were isolated from human OA cartilage and normal cartilage biopsied, and the degree of cartilage degradation was determined by safranin O staining. We found that the expression levels of SHMT-2 and MECP-2 were increased in OA chondrocytes, and 3'UTR reporter assays showed that SHMT-2 and MECP-2 are the direct targets of miR-370 and miR-373, respectively, in human articular chondrocytes. Our experiments showed that miR-370 and miR-373 levels were significantly lower in OA chondrocytes compared to normal chondrocytes. Overexpression of miR-370 or miR-373, or knockdown of SHMT-2 or MECP-2 reduced both MMP-13 expression and apoptotic cell death in cultured OA chondrocytes. In vivo, we found that introduction of miR-370 or miR-373 into the cartilage of mice that had undergone destabilization of the medial meniscus (DMM) surgery significantly reduced the cartilage destruction in this model, whereas introduction of SHMT-2 or MECP-2 increased the severity of cartilage destruction. Together, these results show that miR-370 and miR-373 contribute to the pathogenesis of OA and act as negative regulators of SHMT-2 and MECP-2, respectively.