Wwp2 maintains cartilage homeostasis through regulation of Adamts5

Nat Commun. 2019 Jun 3;10(1):2429. doi: 10.1038/s41467-019-10177-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS5 Protein / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / metabolism
  • Cartilage, Articular / diagnostic imaging
  • Cartilage, Articular / metabolism*
  • Core Binding Factor Alpha 1 Subunit / metabolism*
  • Disease Models, Animal
  • Humans
  • Knee Joint / diagnostic imaging
  • Menisci, Tibial / surgery
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • RNA, Messenger / pharmacology
  • Signal Transduction
  • Skull / diagnostic imaging
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • X-Ray Microtomography
  • Young Adult


  • Core Binding Factor Alpha 1 Subunit
  • RNA, Messenger
  • Runx2 protein, mouse
  • WWP2 protein, human
  • Wwp2 protein, mouse
  • Ubiquitin-Protein Ligases
  • ADAMTS5 Protein
  • Adamts5 protein, mouse