The Vitamin D-Sirt1/PGC1α Axis Regulates Bone Metabolism and Counteracts Osteoporosis.

Abstract

Background: Objective: Vitamin D insufficiency is a major contributor to osteoporosis. This study aimed to elucidate the mechanisms by which the vitamin D-Sirt1/PGC1α axis regulates bone metabolism and counteracts osteoporosis induced by active vitamin D insufficiency.

Methods: Mouse models including Sirt1 transgenic (Sirt1^Tg), Cyp27b1^+/- (active vitamin D deficient), and compound Sirt1^TgCyp27b1^+/- mice were utilized. Bone parameters were assessed by radiography, micro-CT, histology, and immunohistochemistry. In vitro studies used bone marrow-derived mesenchymal stem cells (BM-MSCs). Gene and protein expression were analyzed by RT-PCR and Western blotting. Chromatin immunoprecipitation and luciferase assays investigated transcriptional regulation. Effects of resveratrol supplementation were examined.

Results: 1,25-dihydroxyvitamin D (1,25(OH)₂D) insufficiency caused downregulation of Sirt1 expression, leading to accelerated bone loss. Overexpression of Sirt1 in mesenchymal stem cells corrected bone loss by inhibiting oxidative stress, DNA damage, osteocyte senescence and senescence-associated secretory phenotype, promoting osteoblastic bone formation, and reducing osteoclastic bone resorption. 1,25(OH)₂D₃ transcriptionally upregulated Sirt1 expression in BM-MSCs through vitamin D receptor binding to the Sirt1 gene promoter. Resveratrol, a Sirt1 agonist, attenuated osteoporosis induced by 1,25(OH)₂D insufficiency by modulating the Sirt1/PGC1α axis. Sirt1 interacted with and deacetylated PGC1α, a transcriptional coactivator involved in mitochondrial biogenesis and energy metabolism. Deacetylated PGC1α mediated the effects of Sirt1 on osteogenesis, oxidative stress, and cellular senescence in BM-MSCs.

Conclusion: This study elucidated the critical role of the vitamin D-Sirt1/PGC1α axis in regulating bone metabolism and counteracting osteoporosis induced by active vitamin D insufficiency. The findings highlight the potential of this axis as a therapeutic target for the prevention and treatment of osteoporosis.