| First Author | Yang R | Year | 2023 |
| Journal | Free Radic Biol Med | Volume | 195 |
| Pages | 231-244 | PubMed ID | 36592659 |
| Mgi Jnum | J:332547 | Mgi Id | MGI:7427200 |
| Doi | 10.1016/j.freeradbiomed.2022.12.102 | Citation | Yang R, et al. (2023) 17beta-estradiol plays the anti-osteoporosis role via a novel ESR1-Keap1-Nrf2 axis-mediated stress response activation and Tmem119 upregulation. Free Radic Biol Med 195:231-244 |
| abstractText | Increased oxidative stress and decreased osteoblastic bone formation contribute to estrogen deficiency-induced osteoporosis. However, the role and mechanism of estrogen-deficiency in regulating oxidative stress and osteoblastic activity remain unclear. Here, we showed that estrogen-deficient bone marrow stromal/stem cells (BMSCs) exhibited impaired capacity to combat stress, characterized by increased oxidative stress, shortened cell survival and reduced osteogenic differentiation and bone formation, which were due to a decrease of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 re-activation induced by the pyrazinyl dithiolethione oltipraz significantly rescued the cell phenotype of estrogen-deficient BMSCs in vitro and ex vivo. Mechanistically, we found that 17beta-estradiol/ESR1 (Estrogen Receptor 1) facilitated Nrf2 accumulation, and activated its target genes by competing with Nrf2 for binding to Kelch-like ECH-associated protein 1 (Keap1) via ESR1 containing a highly conserved DLL motif. Of note, oltipraz, an Nrf2 activator, rescued ovariectomy-induced osteoporosis partly by inhibiting oxidative stress and promoting osteoblastic bone formation via Nrf2-induced antioxidant signaling activation and Tmem119 (transmembrane protein 119) upregulation. Conversely, Nrf2 knockout largely blocked the bone anabolic effect of 17beta-estradiol in vivo and ex vivo. This study provides insight into the mechanisms whereby estrogen prevents osteoporosis through promoting osteoblastic bone formation via Nrf2-mediated activation of antioxidant signaling and upregulation of Tmem119, and thus provides evidence for Nrf2 as a potential target for clinical prevention and treatment of menopause-related osteoporosis. |
