Inhibition of Nrf2 degradation alleviates age-related osteoporosis induced by 1,25-Dihydroxyvitamin D deficiency

Previous studies have shown that 1,25(OH)(2)D plays an anti-osteoporosis role by an anti-aging mechanism. Oxidative stress is a key mediator of aging and bone loss; however, whether 1,25(OH)(2)D can exert its anti-osteoporosis effect by inhibiting oxidative stress is unclear. In this study, osteoporosis and the bone aging phenotype induced by 1,25(OH)(2)D deficiency in male mice were significantly rescued in vivo upon the supplementation of oltipraz, an inhibitor of Nrf2 degradation. Increased oxidative stress, cellular senescence and reduced osteogenesis of BM-MSCs from VDR knockout mice were also significantly rescued when the cells were pre-treated with oltipraz. We found that 1,25(OH)(2)D-3 promoted Nrf2 accumulation by inhibiting its ubiquitinproteasome degradation, thus facilitating Nrf2 activation of its transcriptional targets. Mechanistically, 1,25 (OH)(2)D-3 enhances VDR-mediated recruitment of Ezh2 and facilitation of H3K27me3 action at the promoter region of Keap1, thus transcriptionally repressing Keap1. To further validate that the Nrf2-Keap1 pathway serves as the key mediator in the anabolic effect of 1,25(OH)(2)D-3 on bone, Nrf2(-/-)mice, or hBM-MSCs with shRNA-mediated Nrf2-knockdown, were treated with 1,25(OH)(2)D-3; we found that Nrf2 knockout largely blocked the bone anabolic effect of 1,25(OH)(2)D-3 in vivo and ex vivo, and Nrf2 knockdown in hBM-MSCs markedly blocked the role of 1,25(OH)(2)D-3 in inhibiting oxidative stress and promoting osteogenic differentiation and bone formation. This study provides insight into the mechanism whereby 1,25(OH)(2)D-3 postpones age-related osteoporosis via VDR-mediated activation of Nrf2-antioxidant signaling and inhibition of oxidative stress, and thus provides evidence for oltipraz as a potential reagent for clinical prevention and treatment of age-related osteoporosis.

Automated summary

The study demonstrates that 1,25(OH)(2)D may delay age-related osteoporosis by regulating Nrf2-antioxidant signaling pathway, and oltipraz shows potential as a reagent for clinical prevention and treatment of age-related osteoporosis.