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Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing

Bone Research 2022年第3期10卷 469-481页

作者： Mubashir Ahmad Benjamin Thilo Krüger Torsten Kroll Sabine Vettorazzi Ann-Kristin Dorn Florian Mengele Sooyeon Lee Sayantan Nandi Dilay Yilmaz Miriam Stolz Naveen Kumar Tangudu David Carro Vázquez Johanna Pachmayr Ion Cristian Cirstea Maja Vujic Spasic aspasia ploubidou Anita Ignatius Jan Tuckermann Institute of Comparative Molecular Endocrinology(CME) Ulm UniversityHelmholtzstrasse 8/189081 UlmGermany Institute of Orthopedic Research and Biomechanics Ulm UniversityHelmholtzstrasse 1489081 UlmGermany Leibniz Institute on Aging–Fritz Lipmann Institute(FLI) Beutenbergstrasse 11D-07745 JenaGermany Praxisklinik für Orthopädie Unfall-und Neurochirurgie Prof.Bischoff/Dr.Spies/Dr.Mengele89231 Neu-UlmGermany Paracelsus Medizinische Privatuniverstät Institute of PharmacyStrubergasse 215020 SalzburgAustria Department of Endocrinology Ludwig Maximilians University MunichMunich 80336Germany Present address:Institute of Orthopedic Research and Biomechanics Ulm UniversityHelmholtzstrasse 1489081 UlmGermany Present address:UPMC Hillman Cancer Center Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh5115 Center Avenue15232 PittsburghPAUSA Present address:TAmiRNA GmbH Leberstrasse 201110 ViennaAustria

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 si RNA, genetic deletion using the Cre-lox P 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.

关键词： Cdk5 healing expression

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