Wwp2 maintains cartilage homeostasis through regulation of Adamts5.
ADAMTS5 Protein
/ metabolism
Adult
Aged
Aged, 80 and over
Animals
Arthritis, Experimental
/ genetics
Cartilage, Articular
/ diagnostic imaging
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
RNA, Messenger
/ pharmacology
Signal Transduction
Skull
/ diagnostic imaging
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
X-Ray Microtomography
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 06 2019
03 06 2019
Historique:
received:
05
09
2018
accepted:
23
04
2019
entrez:
5
6
2019
pubmed:
5
6
2019
medline:
25
6
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31160553
doi: 10.1038/s41467-019-10177-1
pii: 10.1038/s41467-019-10177-1
pmc: PMC6546747
doi:
Substances chimiques
Core Binding Factor Alpha 1 Subunit
0
RNA, Messenger
0
Runx2 protein, mouse
0
WWP2 protein, human
EC 2.3.2.26
Wwp2 protein, mouse
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
ADAMTS5 Protein
EC 3.4.24.-
Adamts5 protein, mouse
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2429Subventions
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : AR065379
Pays : International
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : AG007996
Pays : International
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP17gm0810008
Pays : International
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP15gm0410001
Pays : International
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : AR050631
Pays : International
Organisme : NIAMS NIH HHS
ID : R01 AR065379
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR050631
Pays : United States
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