Bone marrow ablation demonstrates that estrogen plays an important role in osteogenesis and bone turnover via an antioxidative mechanism

Shi, Chunmin; Wu, Jun; Yan, Quanquan; Wang, Rong; Miao, Dengshun

doi:10.1016/j.bone.2015.05.034

Cited by 23 publications

(19 citation statements)

References 58 publications

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“…Three‐month‐old female mice were ovariectomized (OVX) typically according to the protocol as described . NAC was dissolved in rodent drinking water at a concentration of 1 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

BMI-1 Mediates Estrogen-Deficiency–Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation

Wang

Yang

et al. 2016

Journal of Bone and Mineral Research

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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.

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“…Three‐month‐old female mice were ovariectomized (OVX) typically according to the protocol as described . NAC was dissolved in rodent drinking water at a concentration of 1 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

BMI-1 Mediates Estrogen-Deficiency–Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation

Wang

Yang

et al. 2016

Journal of Bone and Mineral Research

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“…When the amount of bone resorbed by osteoclasts is not fully restored by bone deposited by osteoblasts, this imbalance leads to a net loss in bone mass and strength218. In the present experiments, OVX mice showed an increased expression of ALP in osteoblasts accompanied by increased number of well-round TRAP positive cells compared with that in SHAM group, indicating a relatively higher bone turnover rate519. These led to a significantly increased level of trabecular separation and a significantly decreased percentage of trabecular area in OVX group compared with sham-operated control animals.…”

Section: Discussionmentioning

confidence: 49%

“…The protective effect of estrogen on osteoblasts against apoptosis might be associated with attenuating the generation of ROS51627. NAC, a free radical scavenger, has been demonstrated to protect osteoblasts against hypoxic-stress-induced apoptosis2829.…”

Section: Discussionmentioning

confidence: 99%

“…NAC, a free radical scavenger, has been demonstrated to protect osteoblasts against hypoxic-stress-induced apoptosis2829. Moreover, administration of antioxidants like NAC, as well as estrogens, prevents the OVX induced loss of bone mass34523. In addition, caspase-3 is activated in the apoptotic cell both by extrinsic (death ligand) and intrinsic (mitochondrial) pathways, in which caspase-3 plays a dominant role30.…”

Section: Discussionmentioning

confidence: 99%

“…Recent mechanistic studies have shown that aging and the associated increase in reactive oxygen species (ROS) – the radical forms of oxygen – may act as the chief culprits underpinning the disease mechanism23456. Indeed, the stimulatory effects of gonadectomy on oxidative stress, osteoclastogenesis and osteoblast apoptosis, as well as the loss of bone mass were attenuated by treatment with antioxidants such as NAC or ascorbate, which were similar to estrogens and androgens345.…”

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confidence: 99%

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Ovariectomy upregulated the expression of Peroxiredoxin 1 & 5 in osteoblasts of mice

Feng

Sun

et al. 2016

Sci Rep

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Peroxiredoxin (PRX), a family of peroxidases, is associated with various biological processes such as the detoxification of oxidants and cell apoptosis. Besides, the anti-apoptosis effect of estrogen results partially from its anti-oxidant function. The purpose of this study was to investigate the expression of PRXs in ovariectomy (OVX) mice and the related anti-oxidative mechanism of estrogen. Eight-week-old mice were subjected to ovariectomy. MC3T3-E1 cells were pretreatment with 17b-estradiol and N-acetyl cysteine followed by oxidative injury induced with H2O2. Western blot and real time-PCR were applied to clarify the expressions of PRX1 and caspase-3, with both wild-type and PRX1 knockout MC3T3-E1 cells generated by CRISPR/Cas9 technology. The results showed PRX1 and PRX5 were upregulated in osteoblasts in the proximal tibial metaphysis of ovariectomy mice. Interestingly, PRX1 and PRX5 showed different distribution patterns, with PRX1 mainly accumulated in cell nuclei and PRX5 in the cytoplasm. Gene expression analysis showed significantly reduced expressions of PRX1 and caspase-3 in the pretreatment groups when compared with cells treated with H2O2 alone. Also, a decrease of caspase-3 expressions was observed in PRX1 knockout MC3T3-E1 cells with or without H2O2 in comparison to wild-type cells. These findings suggested that PRX may play important roles in estrogen-deficient osteoporosis. (200 words).

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tBHQ Suppresses Osteoclastic Resorption in Xenogeneic‐Treated Dentin Matrix‐Based Scaffolds

Sun

et al. 2017

Adv Healthcare Materials

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Extracellularmatrix (ECM)-based scaffolds are important for their potential therapeutic application. Treated dentin matrix (TDM), a kind of ECM, seeded with allogeneic dental follicle stem cells (TDM/aDFC) provides a suitable inductive microenvironment for tooth root regeneration. Considering the limited sources, xenogeneic TDM (xTDM) is a possible alternative to allogeneic TDM; however, xTDM-based scaffold presents severe osteolysis and resorption lacunae causing regenerated tooth root failure. Immune response-induced excessive osteoclastogenesis plays a critical role in xenogeneic scaffold osteolysis and resorption. The impact of antioxidant, tert-butylhydroquinone (tBHQ), on xTDM/aDFCs-induced osteoclastogenesis and osteoclastic resorption in vivo and in vitro are investigated. tBHQ upregulates heme oxygenase-1 release and downregulates high mobility group box 1 mRNA expression. mRNA expression of other osteoclast-related genes including nuclear factor-kappa Bp65, receptor activator of nuclear factor kappa-B, nuclear factor of activated T-cells cytoplasmic 1, cathepsin K, and integrin β3, also decreases significantly. Furthermore, tBHQ-treated xTDM/aDFCs scaffolds implanted into rhesus macaques show reduced osteolysis and osteoclastic resorption by microcomputed tomography and tartrate-resistant acid phosphatase staining. tBHQ-induced suppression of xTDM/aDFC-induced osteoclastogenesis and osteoclastic resorption presents a new strategy for the regeneration of biological tooth root and could be applied to the regeneration of other complex tissues and organs.

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Bone marrow ablation demonstrates that estrogen plays an important role in osteogenesis and bone turnover via an antioxidative mechanism

Cited by 23 publications

References 58 publications

BMI-1 Mediates Estrogen-Deficiency–Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation

BMI-1 Mediates Estrogen-Deficiency–Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation

Ovariectomy upregulated the expression of Peroxiredoxin 1 & 5 in osteoblasts of mice

tBHQ Suppresses Osteoclastic Resorption in Xenogeneic‐Treated Dentin Matrix‐Based Scaffolds

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