期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 16, 期 14, 页码 2712-2726出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.48169
关键词
mandibular bone; Sirt1 promoter; mesenchymal stem cells; antioxidant enzymes peroxiredoxin1
资金
- National Key R&D Program of China [2018YFA0800800]
- National Natural Science Foundation of China [81230009, 81730066]
- Canadian Institutes of Health Research (CIHR) [PJT-152963]
It has been reported that 1,25 dihydroxyvitamin D [1,25(OH)(2)D] deficiency leads to the loss of mandibular bone, however the mechanism is unclear. We investigated whether the Sirt1/FOXO3a signaling pathway is involved in this process. Using a 1,25(OH)(2)D deficiency model induced by genetic deletion in mice of 25-hydroxyvitamin D-1 alpha hydroxylase [1 alpha(OH)ase(-/-) mice]. We first documented a sharp reduction of expression levels of Sirt1 in the 1 alpha(OH)ase(-/-) mice in vivo. Next, we demonstrated dose-dependent upregulation of Sirt1 by treatment with exogenous 1,25(OH)(2)D-3 in vitro. We then identified a functional VDR binding site in the Sirt1 promoter. By crossing Prx1-Sirt1 transgenic mice with 1 alpha(OH)ase(-/-) mice we demonstrated that the overexpression of Sirt1 in mesenchymal stem cells (MSCs) greatly improved the 1 alpha(OH)ase(-/-) mandibular bone loss phenotype by increasing osteoblastic bone formation and reducing osteoclastic bone resorption. In mechanistic studies, we showed, in 1 alpha(OH)ase(-/-) mice, decreases of Sirt1 and FoxO3a, an increase in oxidative stress as reflected by a reduction of the antioxidant enzymes peroxiredoxin1 (Prdx1), SOD1 and SOD2 expression, and an increase of markers for osteocyte senescence and senescence associated secretory phenotypes (SASP), including beta-galactosidase (beta-gal), p16, p53 and p21. The targeted overexpression of Sirt1 in the 1 alpha(OH)ase(-/-) mice restored the expression levels of these molecules. Finally, we demonstrated that a Sirt1 agonist can upregulate FOXO3a activity by increasing deacetylation and nuclear translocation. Overall, results from this study support the concept that targeted increases in Sirt1/FOXO3a signaling levels can greatly improve the bone loss caused by 1,25(OH)(2)D deficiency.
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