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

IF 5.9 1区 医学 Q1 ORTHOPEDICS
Journal of Orthopaedic Translation Pub Date : 2025-01-16 eCollection Date: 2025-01-01 DOI:10.1016/j.jot.2024.10.011
Cuicui Yang, Lulu Chen, Xiaoli Guo, Haijian Sun, Dengshun Miao
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引用次数: 0

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 (Sirt1Tg), Cyp27b1+/- (active vitamin D deficient), and compound Sirt1TgCyp27b1+/- 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.

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来源期刊
Journal of Orthopaedic Translation
Journal of Orthopaedic Translation Medicine-Orthopedics and Sports Medicine
CiteScore
11.80
自引率
13.60%
发文量
91
审稿时长
29 days
期刊介绍: The Journal of Orthopaedic Translation (JOT) is the official peer-reviewed, open access journal of the Chinese Speaking Orthopaedic Society (CSOS) and the International Chinese Musculoskeletal Research Society (ICMRS). It is published quarterly, in January, April, July and October, by Elsevier.
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