The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression
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DOI：
10.1038/s41467-019-10753-5
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发表时间：
2019-06-28
影响因子：
16.6
通讯作者：
Chen, Di
中科院分区：
文献类型：
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作者：
Huang, Jian;Zhao, Lan;Chen, Di
骨关节炎（OA）是一种常见的疼痛性疾病。目前OA是无法治愈的，其病因在很大程度上是未知的，部分原因是对OA作为一种全关节疾病的理解有限。在这里，我们报告了两种同源microRNA，miR-204和miR-211，维持关节内稳态以抑制OA发病机制。特异性敲除间充质祖细胞（MPCs）中的miR-204/-211导致Runx 2在多类型关节细胞中积聚，引起全关节变性。具体而言，miR-204/-211功能丧失诱导关节软骨细胞和滑膜细胞中的基质降解蛋白酶，刺激关节软骨破坏。此外，miR-204/-211消融以Runx 2依赖性方式增强NGF表达，并因此过度激活Akt信号传导和MPC增殖，这是包括滑膜增生、骨赘生长和软骨下硬化在内的多发性非软骨性OA病症的基础。重要的是，miR-204/-211缺陷诱导的OA在很大程度上被Runx 2不足所挽救，证实了miR-204/-211-Runx 2轴。此外，关节内施用表达miR-204的腺相关病毒显著减缓OA进展。总体而言，miR-204/-211在维持间充质关节细胞的健康稳态以对抗OA发病机制中是必不可少的。
Osteoarthritis (OA) is a common, painful disease. Currently OA is incurable, and its etiology largely unknown, partly due to limited understanding of OA as a whole-joint disease. Here we report that two homologous microRNAs, miR-204 and miR-211, maintain joint homeostasis to suppress OA pathogenesis. Specific knockout of miR-204/-211 in mesenchymal progenitor cells (MPCs) results in Runx2 accumulation in multi-type joint cells, causing whole-joint degeneration. Specifically, miR-204/-211 loss-of-function induces matrix-degrading proteases in articular chondrocytes and synoviocytes, stimulating articular cartilage destruction. Moreover, miR-204/-211 ablation enhances NGF expression in a Runx2-dependent manner, and thus hyper-activates Akt signaling and MPC proliferation, underlying multiplex non-cartilaginous OA conditions including synovial hyperplasia, osteophyte outgrowth and subchondral sclerosis. Importantly, miR-204/-211-deficiency-induced OA is largely rescued by Runx2 insufficiency, confirming the miR-204/-211-Runx2 axis. Further, intraarticular administration of miR-204-expressing adeno-associated virus significantly decelerates OA progression. Collectively, miR-204/-211 are essential in maintaining healthy homeostasis of mesenchymal joint cells to counteract OA pathogenesis.