Wwp2 maintains cartilage homeostasis through regulation of Adamts5
Wwp2 maintains cartilage homeostasis through regulation of Adamts5
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DOI：
10.1038/s41467-019-10177-1
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发表时间：
2019-06-03
影响因子：
16.6
通讯作者：
Asahara, Hiroshi
中科院分区：
文献类型：
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作者：
Mokuda, Sho;Nakamichi, Ryo;Asahara, Hiroshi
含WW结构域蛋白2（Wwp 2）基因是miR-140的宿主基因，编码Wwp 2蛋白，其是在关节软骨中大量表达的HECT型E3泛素连接酶。然而，其功能仍不清楚。在这里，我们表明，缺乏Wwp 2的小鼠和Wwp 2 E3酶失活的小鼠（Wwp 2-C838 A）表现出加重的自发性和手术诱导的骨关节炎（OA）。与该表型一致，WWP 2表达水平在人OA软骨中下调。我们还确定Runx 2作为Wwp 2底物，Adamts 5作为靶基因，与miR-140相似。Wwp 2-C838 A小鼠的分析显示Wwp 2 E3连接酶活性的丧失导致关节软骨中Runx 2-Adamts 5信号传导的上调。此外，在体外转录的Wwp 2 mRNA注射到小鼠关节降低实验性OA的严重程度。我们认为Wwp 2通过Runx 2多聚泛素化和降解抑制Runx 2诱导的Adamts 5，在保护软骨免受OA中发挥作用。
The WW domain-containing protein 2 (Wwp2) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation.