Wwp2 maintains cartilage homeostasis through regulation of Adamts5

被引：103

作者：

Mokuda, Sho ^{[1
,2
]}

Nakamichi, Ryo ^{[1
]}

Matsuzaki, Tokio ^{[1
]}

Ito, Yoshiaki ^{[3
,4
]}

Sato, Tempei ^{[3
]}

Miyata, Kohei ^{[1
]}

Inui, Masafumi ^{[5
,6
]}

Olmer, Merissa ^{[1
]}

Sugiyama, Eiji ^{[2
]}

Lotz, Martin ^{[1
]}

Asahara, Hiroshi ^{[1
,3
]}

机构：

[1] Scripps Res Inst, Dept Mol Med, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Hiroshima Univ Hosp, Dept Clin Immunol & Rheumatol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348551, Japan

[3] TMDU, Grad Sch Med & Dent Sci, Dept Syst BioMed, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138510, Japan

[4] TMDU, Inst Res, Res Core, Res Facil Cluster,Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138510, Japan

[5] Meiji Univ, Sch Agr, Dept Life Sci, Lab Anim Regenerat Systemol,Tama Ku, 1-1-1 Higashimita, Kawasaki, Kanagawa 2148571, Japan

[6] Meiji Univ, Int Inst Bioresource Res, Tama Ku, 1-1-1 Higashimita, Kawasaki, Kanagawa 2148571, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

UBIQUITIN LIGASES; HECT FAMILY; OSTEOARTHRITIS; EXPRESSION; RNA; PROTEIN; BONE; DEGRADATION; MATRIX; RUNX2;

D O I：

10.1038/s41467-019-10177-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：13

共 61 条

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