miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively.
miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively.
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DOI：
10.1111/acel.12363
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发表时间：
2015-10
期刊：
影响因子：
7.8
通讯作者：
Jin EJ
中科院分区：
文献类型：
--
作者：
Song J;Kim D;Chun CH;Jin EJ
本研究的目的是确定慢性退行性关节疾病骨关节炎（OA）期间单碳代谢和DNA甲基化之间关联的机制。从人OA软骨中分离关节软骨细胞，并对正常软骨进行活组织检查，采用红花素O染色法测定软骨降解程度。我们发现SHMT-2和MECP-2在OA软骨细胞中的表达水平升高，3'UTR报告基因检测显示SHMT-2和MECP-2分别是人关节软骨细胞中miR-370和miR-373的直接靶点。我们的实验表明，与正常软骨细胞相比，OA软骨细胞中的miR-370和miR-373水平显著降低。过表达miR-370或miR-373，或敲低SHMT-2或MECP-2，均可降低培养的OA软骨细胞中MMP-13的表达和凋亡细胞的死亡。在体内，我们发现将miR-370或miR-373引入到经历内侧半月板失稳（DMM）手术的小鼠软骨中可以显著减少该模型中的软骨破坏，而引入SHMT-2或MECP-2则增加了软骨破坏的严重程度。总之，这些结果表明miR-370和miR-373参与OA的发病机制，并分别作为SHMT-2和MECP-2的负调节因子。
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.