2. Academic Validation
  3. 17β-estradiol plays the anti-osteoporosis role via a novel ESR1-Keap1-Nrf2 axis-mediated stress response activation and Tmem119 upregulation

17β-estradiol plays the anti-osteoporosis role via a novel ESR1-Keap1-Nrf2 axis-mediated stress response activation and Tmem119 upregulation

  • Free Radic Biol Med. 2022 Dec 30;S0891-5849(22)01136-4. doi: 10.1016/j.freeradbiomed.2022.12.102.
Renlei Yang 1,  Jie Li 2,  Jing Zhang 3,  Qi Xue 2,  Ran Qin 2,  Rong Wang 2,  David Goltzman 4,  Dengshun Miao 5
Affiliations

Affiliations

  • 1 Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China; State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China. Electronic address: yang_renlei@126.com.
  • 2 State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
  • 3 Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 4 Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, H4A 3J1, Canada.
  • 5 Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China; State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China. Electronic address: dsmiao@njmu.edu.cn.
PMID: 36592659 DOI: 10.1016/j.freeradbiomed.2022.12.102
Abstract

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 17β-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 17β-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.

Keywords

Estrogen; Keap1-Nrf2 interaction; Osteoporosis; Stress response; Tmem119.

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