Wwp2 maintains cartilage homeostasis through regulation of Adamts5

Sho Mokuda, Ryo Nakamichi, Tokio Matsuzaki, Yoshiaki Ito, Tempei Sato, Kohei Miyata, Masafumi Inui, Merissa Olmer, Eiji Sugiyama, Martin Lotz and Hiroshi Asahara ()
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Sho Mokuda: The Scripps Research Institute
Ryo Nakamichi: The Scripps Research Institute
Tokio Matsuzaki: The Scripps Research Institute
Yoshiaki Ito: Tokyo Medical and Dental University (TMDU)
Tempei Sato: Tokyo Medical and Dental University (TMDU)
Kohei Miyata: The Scripps Research Institute
Masafumi Inui: Meiji University
Merissa Olmer: The Scripps Research Institute
Eiji Sugiyama: Hiroshima University Hospital
Martin Lotz: The Scripps Research Institute
Hiroshi Asahara: The Scripps Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10177-1

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