Active vitamin D protects against osteoporosis by promoting VDR-dependent CDK2 transcription and P27 degradation

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Abstract
Objective: Osteoporosis is associated with reduced active vitamin D, but the molecular basis remains incompletely understood. This study investigated how active vitamin D preserves skeletal homeostasis and prevents bone loss. Design: Experimental mechanistic study using genetically modified mouse models and bone marrow mesenchymal stem cells (BMSCs). Methods: Mice with reduced active vitamin D production were examined for bone mass, skeletal aging, and osteogenic capacity. Mouse and human BMSCs were used to assess proliferation, osteogenic differentiation, and molecular signaling. Gene expression, protein turnover, and pathway analyses determined how active vitamin D regulates cell-cycle control in skeletal progenitors. Genetic deletion studies tested the functional contribution of P27 to bone loss. Results: Active vitamin D protected against osteoporosis by activating a vitamin D receptor (VDR)-dependent pathway that increased cyclin-dependent kinase 2 (CDK2) expression and promoted P27 degradation in BMSCs. Loss of this signaling caused P27 accumulation, reduced stem-cell proliferation, impaired osteogenic differentiation, and enhanced skeletal senescence, leading to bone loss. Active vitamin D promoted P27 phosphorylation at threonine 187 and its degradation via the ubiquitin-proteasome pathway. Importantly, P27 deletion partially rescued the osteoporotic phenotype in mice with reduced active vitamin D production. Conclusions: Active vitamin D maintains bone integrity through a VDR-dependent mechanism that enhances CDK2 expression and promotes P27 degradation in BMSCs. These findings identify a previously unrecognized mechanism linking vitamin D signaling to skeletal aging and suggest that targeting P27 turnover may offer a therapeutic strategy, provided tissue-specific approaches mitigate the oncogenic risks of P27 manipulation.
Funding Information
  • National Natural Science Foundation of China (82172504)
  • National Natural Science Foundation of China (82302935)

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