Xiong Yi, Zhang Yixin, Xin Na, Yuan Ying, Zhang Qin, Gong Ping, Wu Yingying
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Steroid Biochem Mol Biol. 2017 Nov;174:153-160. doi: 10.1016/j.jsbmb.2017.08.014. Epub 2017 Aug 30.
Diabetes mellitus (DM) remarkably affects bone metabolism and causes multiple skeletal disorders, which are associated with the increased oxidative stress that activates Forkhead family of transcription factors (FoxOs). 1α,25-Dihydroxy vitamin D (1,25(OH)D), the hormonally active form of vitamin D, plays a potential role in the prevention of glucose tolerance. However, its mechanism of action in high glucose-induced energy disorders remains unclear. In vitro study shows that 1,25(OH)D promotes osteogenesis in high glucose-induced oxidative stress mainly results from increased osteoblasts proliferation and decreased apoptosis. Cells treated with 1,25(OH)D exhibit an increased osteogenic differentiation capacity and an elevated level of osteogenic phenotype (i.e. alkaline phosphatase, collagen 1, osteocalcin, and osteopontin). We also found that the effect of 1,25(OH)D on osteogenesis is achieved by FoxO1 inactivation and nuclear exclusion through PI3K/Akt pathway in a time- and dose-dependent manner. Moreover, the diversion of β-catenin from FoxO1- to Wnt/TCF4-mediated transcription was indirectly promoted by the inactivation of FoxO1. These data together reveals that the activated Wnt/β-catenin signaling is involved in the regulatory action of 1,25(OH)D on osteogenesis in oxidative stress. This study also provides a novel understanding of the effect of 1,25(OH)D on skeleton in oxidative stress condition.
糖尿病（DM）显著影响骨代谢并引发多种骨骼疾病，这些疾病与激活叉头转录因子家族（FoxOs）的氧化应激增加有关。1α,25-二羟基维生素D（1,25(OH)D）是维生素D的激素活性形式，在预防葡萄糖耐量方面发挥潜在作用。然而，其在高糖诱导的能量紊乱中的作用机制尚不清楚。体外研究表明，1,25(OH)D在高糖诱导的氧化应激中促进成骨作用，主要是由于成骨细胞增殖增加和凋亡减少。用1,25(OH)D处理的细胞表现出成骨分化能力增强和成骨表型水平升高（即碱性磷酸酶、胶原蛋白1、骨钙素和骨桥蛋白）。我们还发现，1,25(OH)D对成骨的作用是通过PI3K/Akt途径使FoxO1失活并从细胞核中排出，呈时间和剂量依赖性。此外，FoxO1的失活间接促进了β-连环蛋白从FoxO1介导的转录向Wnt/TCF4介导的转录的转变。这些数据共同表明，激活的Wnt/β-连环蛋白信号通路参与了1,25(OH)D在氧化应激中对成骨的调节作用。本研究还为1,25(OH)D在氧化应激条件下对骨骼的影响提供了新的认识。
