MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin
MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin
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MiR-146b 通过靶向 α-2-巨球蛋白加速骨关节炎进展
DOI：
10.18632/aging.102160
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发表时间：
2019-08-31
期刊：
影响因子：
5.2
通讯作者：
Cai, Daozhang
中科院分区：
文献类型：
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作者：
Liu, Xin;Liu, Liangliang;Cai, Daozhang
骨关节炎（OA）是一种以软骨细胞外基质（ECM）降解为特征的与年龄相关的慢性退行性疾病。先前的研究表明microRNAs（miRNAs）与OA相关，但miR-146 b在OA中的作用尚不清楚。本研究的目的是确定miR-146 b在OA进展中的作用。在用miRNA转染并用IL-1β处理的小鼠软骨细胞中研究miR-146 b对ECM降解的影响。通过实时RT-PCR、ELISA和Western印迹评估转染细胞中的细胞活力和蛋白水解酶的表达水平。我们发现，软骨细胞中miR-146 b表达的下调通过影响其靶向α-2-巨球蛋白（A2 M），显著抑制IL-1β诱导的caspase活化和蛋白水解酶表达。荧光素酶报告基因检测证实，A2 M mRNA在软骨细胞中受到miR-146 b的负调控。关节内注射miR-146 b对抗miR-146 b通过抑制软骨蛋白聚糖降解有效地保护小鼠免于DMM诱导的骨关节炎的进展。我们的研究表明，miR-146 b通过直接靶向A2 M表达，提高蛋白水解酶的产生并刺激软骨细胞凋亡，在损伤诱导的骨关节炎的进展中起关键作用，miR-146 b和A2 M可能是治疗靶点。
Osteoarthritis (OA) is an aging-related chronic degenerative disease characterized by the degradation of chondrocyte extracellular matrix (ECM). Previous studies have suggested that microRNAs (miRNAs) are associated with OA, but the role of miR-146b in OA remains unclear. The aim of this study was to determine the role of miR-146b in OA progression. The effect of miR-146b on ECM degradation were studied in mouse chondrocytes transfected with miRNA and treated with IL-1β. Cell viability and the expression levels of proteolytic enzymes in the transfected cells were assessed by real-time RT-PCR, ELISA and Western blots. We found downregulation of miR-146b expression in chondrocytes dramatically inhibited IL-1β-induced caspase activation and proteolytic enzyme expression via influencing its targeted Alpha-2-macroglobulin (A2M). Luciferase reporter assays confirmed that A2M mRNA was negatively regulated by miR-146b in chondrocytes. Intra-articular injection of antago-miR-146b against miR-146b effectively protected mice from the progression of DMM-induced osteoarthritis by inhibiting cartilage proteoglycan degradation. Our study indicates that miR-146b plays a critical role in the progression of injury-induced osteoarthritis by directly targeting A2M expression to elevate the proteolytic enzyme production and stimulate chondrocytes apoptosis, and miR-146b as well as A2M could be therapeutic targets.