SIRT1/FOXO3a axis plays an important role in the prevention of mandibular bone loss induced by 1,25(OH)2D deficiency

Autor: Haiyun Chen, David Goltzman, Dengshun Miao, Guoping Wu, Qian Tan, Xiaoqing Hu, Renlei Yang
Rok vydání: 2020
Předmět:
Genetically modified mouse
Senescence
medicine.medical_specialty
animal structures
antioxidant enzymes peroxiredoxin1
Alveolar Bone Loss
Drug Evaluation
Preclinical
SOD2
Mice
Transgenic
Mandible
medicine.disease_cause
mandibular bone
Applied Microbiology and Biotechnology
Antioxidants
Bone resorption
03 medical and health sciences
Sirtuin 1
Downregulation and upregulation
Osteogenesis
Internal medicine
medicine
Animals
Humans
Molecular Biology
Cells
Cultured
Cellular Senescence
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
mesenchymal stem cells
0303 health sciences
Chemistry
Forkhead Box Protein O3
Cell Biology
Vitamin D Deficiency
Endocrinology
medicine.anatomical_structure
Resveratrol
Osteocyte
Receptors
Calcitriol
Sirt1 promoter
Signal transduction
Oxidative stress
Research Paper
Developmental Biology
Zdroj: International Journal of Biological Sciences
ISSN: 1449-2288
Popis: It has been reported that 1,25 dihydroxyvitamin D [1,25(OH)2D] 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)2D deficiency model induced by genetic deletion in mice of 25-hydroxyvitamin D-1α hydroxylase [1α(OH)ase-/- mice]. We first documented a sharp reduction of expression levels of Sirt1 in the 1α(OH)ase-/- mice in vivo. Next, we demonstrated dose-dependent upregulation of Sirt1 by treatment with exogenous 1,25(OH)2D3 in vitro. We then identified a functional VDR binding site in the Sirt1 promoter. By crossing Prx1-Sirt1 transgenic mice with 1α(OH)ase-/- mice we demonstrated that the overexpression of Sirt1 in mesenchymal stem cells (MSCs) greatly improved the 1α(OH)ase-/- mandibular bone loss phenotype by increasing osteoblastic bone formation and reducing osteoclastic bone resorption. In mechanistic studies, we showed, in 1α(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 β-galactosidase (β-gal), p16, p53 and p21. The targeted overexpression of Sirt1 in the 1α(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)2D deficiency.
Databáze: OpenAIRE
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