Qiao Wanxin, Yu Shuxiang, Sun Haijian, Chen Lulu, Wang Rong, Wu Xuan, Goltzman David, Miao Dengshun
Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Key Laboratory for Aging & Disease Nanjing, China.
Nanjing Medical University Nanjing, China.
Am J Transl Res. 2020 Feb 15;12(2):507-518. eCollection 2020.
We investigated the role of insufficiency of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)D] in age-related bone loss. We employed mice with heterozygous deletion of , the gene encoding the enzyme that synthesizes 1,25(OH)D, as a model for 1,25(OH)D insufficiency and compared the phenotype of lumber vertebrae from 3-, 9- and 18-month-old mice and their wild-type littermates. We found that in wild-type mice, bone mineral density, bone volume, and 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 mice which had significantly lower serum 1,25(OH)D levels. We then assessed the effect of 1,25(OH)D haploinsufficiency on oxidative stress and DNA damage, cell senescence and senescence-associated secretory phenotype (SASP) in 9-month-old wild-type and mice. Our results demonstrated that, in 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)D 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.
我们研究了活性形式的维生素D，即1,25-二羟基维生素D[1,25(OH)D]缺乏在与年龄相关的骨质流失中的作用。我们采用编码合成1,25(OH)D的酶的基因杂合缺失的小鼠作为1,25(OH)D缺乏的模型，并比较了3个月、9个月和18个月大的该基因杂合缺失小鼠及其野生型同窝小鼠腰椎的表型。我们发现，在野生型小鼠中，骨矿物质密度、骨体积和蛋白质表达水平随年龄增长而逐渐下降，同时伴有成骨细胞骨形成减少和破骨细胞骨吸收增加，然而，这些与年龄相关的骨骼改变在血清1,25(OH)D水平显著较低的该基因杂合缺失小鼠中更为严重。然后，我们评估了1,25(OH)D单倍剂量不足对9个月大的野生型和该基因杂合缺失小鼠氧化应激和DNA损伤、细胞衰老以及衰老相关分泌表型（SASP）的影响。我们的结果表明，与野生型同窝小鼠相比，该基因杂合缺失小鼠的氧化应激和DNA损伤参数显著增加，而抗氧化酶的表达水平显著下调；骨组织中衰老的骨细胞和骨髓间充质干细胞的百分比，以及SASP分子和p16、p19和p53蛋白的表达水平均显著增加。综上所述，本研究结果表明，1,25(OH)D缺乏通过增加氧化应激和DNA损伤、诱导骨细胞衰老和SASP，进而抑制成骨细胞骨形成并刺激破骨细胞骨吸收，加速了与年龄相关的骨质流失。
