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

Abstract

Previous studies have shown that 1,25(OH)2D 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)2D 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)2D 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)2D3 promoted Nrf2 accumulation by inhibiting its ubiquitin-proteasome degradation, thus facilitating Nrf2 activation of its transcriptional targets. Mechanistically, 1,25(OH)2D3 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)2D3 on bone, Nrf2-/- mice, or hBM-MSCs with shRNA-mediated Nrf2-knockdown, were treated with 1,25(OH)2D3; we found that Nrf2 knockout largely blocked the bone anabolic effect of 1,25(OH)2D3 in vivo and ex vivo, and Nrf2 knockdown in hBM-MSCs markedly blocked the role of 1,25(OH)2D3 in inhibiting oxidative stress and promoting osteogenic differentiation and bone formation. This study provides insight into the mechanism whereby 1,25(OH)2D3 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.

• Authors: Renlei Yang, Jiao Zhang, Jie Li, Ran Qin, Jie Chen, Rong Wang, David Goltzman, Dengshun Miao
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 178 Pg. 246-261 (01 2022) ISSN: 1873-4596 [Electronic] United States
• PMID: 34890768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Receptors, Calcitriol
• Vitamin D
• 1,25-dihydroxyvitamin D

Topics

• Animals
• Kelch-Like ECH-Associated Protein 1 (genetics)
• Male
• Mice
• NF-E2-Related Factor 2 (genetics, metabolism)
• Osteogenesis
• Osteoporosis (drug therapy, genetics)
• Receptors, Calcitriol (metabolism)
• Vitamin D (analogs & derivatives)