1α,25-Dihydroxyvitamin D₃ promotes osteogenesis by promoting Wnt signaling pathway

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 D₃ (1,25(OH)₂D₃), 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)₂D₃ promotes osteogenesis in high glucose-induced oxidative stress mainly results from increased osteoblasts proliferation and decreased apoptosis. Cells treated with 1,25(OH)₂D₃ 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)₂D₃ 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)₂D₃ on osteogenesis in oxidative stress. This study also provides a novel understanding of the effect of 1,25(OH)₂D₃ on skeleton in oxidative stress condition.