Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing.
Journal
Bone research
ISSN: 2095-4700
Titre abrégé: Bone Res
Pays: China
ID NLM: 101608652
Informations de publication
Date de publication:
06 Apr 2022
06 Apr 2022
Historique:
received:
14
04
2021
accepted:
21
12
2021
revised:
10
12
2021
entrez:
6
4
2022
pubmed:
7
4
2022
medline:
7
4
2022
Statut:
epublish
Résumé
Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.
Identifiants
pubmed: 35383146
doi: 10.1038/s41413-022-00195-z
pii: 10.1038/s41413-022-00195-z
pmc: PMC8983726
doi:
Types de publication
Journal Article
Langues
eng
Pagination
33Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC1149 (INST 40/492-2)
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC1149 (INST 40/492-1)
Informations de copyright
© 2022. The Author(s).
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