1,25-Dihydroxyvitamin D insufficiency accelerates age-related bone loss by increasing oxidative stress and cell senescence.

Abstract

We investigated the role of insufficiency of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D] in age-related bone loss. We employed mice with heterozygous deletion of Cyp27b1, the gene encoding the enzyme that synthesizes 1,25(OH)2D, as a model for 1,25(OH)2D insufficiency and compared the phenotype of lumber vertebrae from 3-, 9- and 18-month-old Cyp27b1+/- mice and their wild-type littermates. We found that in wild-type mice, bone mineral density, bone volume, and Cyp27b1 protein expression levels decreased progressively with age, accompanied by declining osteoblastic bone formation and increasing osteoclastic bone resorption, however these age-related skeletal alterations were more severe in Cyp27b1+/- mice which had significantly lower serum 1,25(OH)2D levels. We then assessed the effect of 1,25(OH)2D haploinsufficiency on oxidative stress and DNA damage, cell senescence and senescence-associated secretory phenotype (SASP) in 9-month-old wild-type and Cyp27b1+/- mice. Our results demonstrated that, in Cyp27b1+/- mice compared with their wild-type littermates, the parameters of oxidative stress and DNA damage were significantly increased, whereas the expression levels of antioxidant enzymes were significantly down-regulated; the percentage of senescent osteocytes and bone marrow mesenchymal stem cells, and the expression levels of SASP molecules and p16, p19 and p53 proteins were all significantly increased in bone tissues. Taken together, the results of this study indicate that 1,25(OH)2D insufficiency accelerates age-related bone loss by increasing oxidative stress and DNA damage, inducing bone cell senescence and SASP, and subsequently inhibiting osteoblastic bone formation while stimulating osteoclastic bone resorption.

• Authors: Wanxin Qiao, Shuxiang Yu, Haijian Sun, Lulu Chen, Rong Wang, Xuan Wu, David Goltzman, Dengshun Miao
• Journal: American journal of translational research (Am J Transl Res) Vol. 12 Issue 2 Pg. 507-518 ( 2020) ISSN: 1943-8141 [Print] United States
• PMID: 32194899 (Publication Type: Journal Article)
• Copyright: AJTR Copyright © 2020.