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Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERα
Article first published online: 14 DEC 2009
DOI: 10.1359/jbmr.091017
Copyright © 2010 American Society for Bone and Mineral Research
Additional Information
How to Cite
Almeida, M., Martin-Millan, M., Ambrogini, E., Bradsher, R., Han, L., Chen, X.-D., Roberson, P. K., Weinstein, R. S., O'Brien, C. A., Jilka, R. L. and Manolagas, S. C. (2010), Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERα. J Bone Miner Res, 25: 769–781. doi: 10.1359/jbmr.091017
Publication History
- Issue published online: 9 APR 2010
- Article first published online: 14 DEC 2009
- Accepted manuscript online: 27 JAN 2010 12:00AM EST
- Manuscript Accepted: 9 OCT 2009
- Manuscript Revised: 31 JUL 2009
- Manuscript Received: 27 MAR 2009
References
- 1. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000; 21: 115–137.
- 2, , . Sex steroids and bone. Recent Prog Horm Res. 2002; 57: 385–409.
- 3, , , , , . Kinase-mediated transcription, activators of nongenotropic estrogen-like signaling (ANGELS), and osteoporosis: a different perspective on the HRT dilemma. Kidney Int Suppl. 2004; 91: S41–49.
- 4, , , et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992; 257: 88–91.
- 5, , , et al. Attenuation of the self-renewal of transit amplifying osteoblast progenitors in the murine bone marrow by 17β-estradiol. J Clin Invest. 2001; 107: 803–812.
- 6, , , et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001; 104: 719–730.
- 7, , , et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science. 2002; 298: 843–846.
- 8, , , et al. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest. 2003; 111: 1651–1664.
- 9, , , et al. Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti-Versus Pro-apoptotic Effects of Estrogens. J Biol Chem. 2005; 280: 4632–4638.
- 10, , , , , . Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow: evidence for autonomy from factors released during bone resorption. J Clin Invest. 1998; 101: 1942–1950.
- 11, , , et al. Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis. Proc Natl Acad Sci U S A. 2004; 101: 6653–6658.
- 12, , . Cross-talk between bone morphogenic proteins and estrogen receptor signaling. Endocrinology. 2002; 143: 2635–2642.
- 13, , , , , . Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor. Mol Cell Biol. 2007; 27: 1516–1530.
- 14. BMP and BMP inhibitors in bone. Ann N Y Acad Sci. 2006; 1068: 19–25.Direct Link:
- 15, , . Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev. 2003; 24: 218–235.
- 16, , . Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev. 2000; 21: 393–411.
- 17, , , et al. Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res. 2000; 15: 663–673.Direct Link:
- 18, , . Smad transcription factors. Genes Dev. 2005; 19: 2783–2810.
- 19, . Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003; 113: 685–700.
- 20, . Specificity and versatility in TGF-β signaling through Smads. Annu Rev Cell Dev Biol. 2005; 21: 659–693.
- 21, , , , . Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell. 2007; 25: 441–454.
- 22, , . Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature. 1997; 389: 618–622.
- 23, , , . Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev. 2003; 17: 3023–3028.
- 24, , . In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis. Genes Dev. 2004; 18: 1482–1494.
- 25, , , et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007; 282: 27285–27297.
- 26, , , et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005; 122: 221–233.
- 27, , , , , . An estrogen receptor (ER) α deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol. 2002; 16: 2188–2201.
- 28, . Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem. 2002; 277: 4883–4891.
- 29, , , , , . Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes. Development. 2000; 127: 4277–4291.
- 30, , , . Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998; 102: 274–282.
- 31, , , et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest. 2002; 109: 1041–1048.
- 32, , , et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell. 2007; 131: 980–993.
- 33, , , , . Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res. 1998; 13: 793–802.Direct Link:
- 34, . Species differences in growth requirements for bone marrow stromal fibroblast colony formation in vitro. Calcif Tissue Int. 1996; 59: 265–270.
- 35, , , et al. Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors α and β. Mol Biol Cell. 2004; 15: 1262–1272.
- 36, , , , . Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by β-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem. 2005; 280: 41342–41351.
- 37, , , . Nickel induces increased oxidants in intact cultured mammalian cells as detected by dichlorofluorescein fluorescence. Toxicol Appl Pharmacol. 1993; 120: 29–36.
- 38, , , , , . Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999; 104: 1363–1374.
- 39, , , , . Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest. 1996; 97: 1732–1740.
- 40, , , et al. Skeletal effects of estrogen are mediated by opposing actions of classical and non-classical estrogen receptor pathways. J Bone Miner Res. 2005; 20: 1992–2001.Direct Link:
- 41, , , , . Default neural induction: neuralization of dissociated Xenopus cells is mediated by Ras/MAPK activation. Genes Dev. 2005; 19: 1022–1027.
- 42, , . The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling. J Biol Chem. 2001; 276: 36869–36872.
- 43, . Perspective: Nonreproductive Sites of Action of Reproductive Hormones. Endocrinology. 2001; 142: 2200–2204.
- 44, . Extranuclear steroid receptors: nature and actions. Endocr Rev. 2007; 28: 726–741.
- 45, , , et al. Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-β in bone remodeling in females but not in males. Bone. 2002; 30: 18–25.
- 46, , , . Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERβ-null mutant. Proc Natl Acad Sci USA. 2008; 105: 2433–2438.
- 47, , , , , . Endogenous TNFα lowers maximum peak bone mass and inhibits osteoblastic Smad activation through NF-κB. J Bone Miner Res. 2007; 22: 646–655.Direct Link:
- 48, , , et al. Impact on Bone of an Estrogen Receptor-α Gene Loss of Function Mutation. J Clin Endocrinol Metab. 2008; 93: 3088–3096.
- 49, , , . Tibio-fibular complex and knee joint, Fig. 7. In Micro-Tomographic Atlas of the Mouse Skeleton. New York, NY: Springer, 2007: 177.
- 50, . Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol. 2004; 20: 285–308.
- 51, . FGF-4 and BMP-2 have opposite effects on limb growth. Nature. 1993; 361: 68–71.
- 52, , , . Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell. 1997; 90: 247–255.
- 53, , , et al. Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells. J Bone Miner Res. 2003; 18: 827–835.Direct Link:
- 54, . Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. Endocrinology. 2005; 146: 3428–3437.
- 55, , . Differential growth factor control of bone formation through osteoprogenitor differentiation. Bone. 2004; 34: 402–411.
- 56, , , , . Exposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesis. J Bone Miner Res. 2002; 17: 394–405.Direct Link:
- 57, , , et al. Estrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) α or β. Endocrinology. 2002; 143: 2349–2356.
- 58, , , et al. Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone. 1998; 22: 201–209.

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