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.

The Polycomb Protein Bmi1 Plays a Crucial Role in the Prevention of 1,25(OH)2D Deficiency-Induced Bone Loss

“…(18) Oxidative stress levels of osteon structures are increased with age (36) and mouse models of osteoporosis are usually accompanied by increased oxidative stress. (37) In the current study, our results suggest that overexpression of Bmi1 in MSCs corrects 1,25(OH) 2 D 3 deficiency-induced bone loss by inactivating p16 and p19 pathways, suppressing oxidative stress and DNA damage and reducing bone cell senescence and SASP. Nevertheless, the detailed mechanism whereby Bmi1 inhibits oxidative stress needs to be further determined.…”

“…It has been reported that abnormal ROS elevation occurs in Bmi1 knockout mice, and N‐acetylcysteine (NAC) supplementation may correct the premature aging phenotype of Bmi1 null mice . Oxidative stress levels of osteon structures are increased with age and mouse models of osteoporosis are usually accompanied by increased oxidative stress . In the current study, our results suggest that overexpression of Bmi1 in MSCs corrects 1,25(OH) 2 D 3 deficiency‐induced bone loss by inactivating p16 and p19 pathways, suppressing oxidative stress and DNA damage and reducing bone cell senescence and SASP.…”

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

“…In this study, we noted that Bmi1 overexpression in MSCs could not rescue completely Bmi1 global deficiency‐induced skeletal growth retardation and osteoporotic phenotypes, although it can accelerate skeletal growth and osteoblastic bone formation through stimulating the osteogenesis of BM‐MSCs in WT mice. It may be related to Bmi1 gene widely expression in embryonic stem cells, placenta, thymus, heart, testicles, and brain , especially, not only in MSCs , but also in lymphocytes . Our previous findings demonstrate that overexpression of Bmi1 only in lymphocytes stimulates osteogenesis of BM‐MSCs by releasing osteogenic factors and lowering ROS levels, thereby accelerating osteogenic bone formation , suggesting that overexpression of Bmi1 in lymphocytes can improve the osteogenic microenvironment and stimulate osteogenesis.…”

1,25‐dihydroxyvitamin D deficiency accelerates alveolar bone loss independent of aging and extracellular calcium and phosphorus

“…42,43 We recently also demonstrated that B lymphoma Mo-MLV insertion region 1 (Bmi-1) overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and receptor activator of nuclear factor-kappa B ligand (RANKL) production. 44 It has been reported that VDR has an effect on potent osteoclastogenic cytokines, including IL-1, in vitro. 45 These cytokines not only influence systemic bone remodeling but also act locally to compromise the tissue response to periodontal diseases.…”