title: BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.
abstract: Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and Eμ-BMI-1 transgenic mice with BMI-1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and RANKL production in T cells, thus enhancing osteoclastogenesis and accelerating bone loss. This study clarifies a novel mechanism regulating estrogen deficiency-induced bone loss. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Human Anatomy, School of Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Renlei
authors.initials: R
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xichao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D063150:Polycomb Repressive Complex 1; D000111:Acetylcysteine
keywords: BMI-1; BONE LOSS; OVARIECTOMY; OXIDATIVE STRESS; T CELL ACTIVATION