Estrogens decrease osteoclast number by attenuating mitochondria oxidative phosphorylation and ATP production in early osteoclast precursors.

Tytuł:: Estrogens decrease osteoclast number by attenuating mitochondria oxidative phosphorylation and ATP production in early osteoclast precursors.
Autorzy:: Kim HN; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Ponte F; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Nookaew I; Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, USA.
Ucer Ozgurel S; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Marques-Carvalho A; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal.
Iyer S; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, USA.
Warren A; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Aykin-Burns N; Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, USA.
Krager K; Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, USA.
Sardao VA; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal.
Han L; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
de Cabo R; Translational Gerontology Branch, NIA, NIH, Baltimore, MD, USA.
Zhao H; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Jilka RL; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.
Manolagas SC; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA.; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, USA.; Central Arkansas Veterans Healthcare System, Little Rock, AR, 72205, USA.
Almeida M; Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, 4301 W. Markham St. #587, Little Rock, 72205-7199, USA. .; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, USA. .; Central Arkansas Veterans Healthcare System, Little Rock, AR, 72205, USA. .
Źródło:: Scientific reports [Sci Rep] 2020 Jul 20; Vol. 10 (1), pp. 11933. Date of Electronic Publication: 2020 Jul 20.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms:: Oxidative Phosphorylation*
Adenosine Triphosphate/*biosynthesis
Estrogens/*metabolism
Mitochondria/*metabolism
Monocyte-Macrophage Precursor Cells/*metabolism
Osteoclasts/*metabolism
Animals ; Apoptosis/drug effects ; Biomarkers ; Bone Density ; Bone and Bones/diagnostic imaging ; Bone and Bones/metabolism ; Bone and Bones/pathology ; Cell Count ; Cell Differentiation ; Cells, Cultured ; Estrogens/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Mice ; Mice, Knockout ; Mitochondria/drug effects ; Monocyte-Macrophage Precursor Cells/cytology ; Monocyte-Macrophage Precursor Cells/drug effects ; Osteoclasts/cytology ; Osteoclasts/drug effects ; Osteogenesis/drug effects ; Signal Transduction
References:: Manolagas, S. C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21, 115–137 (2000). (PMID: 10782361)
Almeida, M. et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol. Rev. 97, 135–187. https://doi.org/10.1152/physrev.00033.2015 (2017). (PMID: 10.1152/physrev.00033.201527807202)
Manolagas, S. C. Steroids and osteoporosis: the quest for mechanisms. J. Clin. Invest. 123, 1919–1921. https://doi.org/10.1172/JCI68062 (2013). (PMID: 10.1172/JCI68062236357903635743)
Hughes, D. E. et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-b. Nat. Med. 2, 1132–1136 (1996). (PMID: 10.1038/nm1096-1132)
Manolagas, S. C., O’Brien, C. A. & Almeida, M. The role of estrogen and androgen receptors in bone health and disease. Nat. Rev. Endocrinol. 9, 699–712. https://doi.org/10.1038/nrendo.2013.179 (2013). (PMID: 10.1038/nrendo.2013.179240423283971652)
Vanderschueren, D. et al. Sex steroid actions in male bone. Endocr. Rev. 35, 906–960. https://doi.org/10.1210/er.2014-1024 (2014). (PMID: 10.1210/er.2014-1024252028344234776)
Nakamura, T. et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130, 811–823 (2007). (PMID: 10.1016/j.cell.2007.07.025)
Martin-Millan, M. et al. The estrogen receptor alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol. Endocrinol. 24, 323–334 (2010). (PMID: 10.1210/me.2009-0354)
Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649. https://doi.org/10.1038/nrg1122 (2003). (PMID: 10.1038/nrg112212897775)
Ishii, K. A. et al. Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat. Med. 15, 259–266 (2009). (PMID: 10.1038/nm.1910)
Indo, Y. et al. Metabolic regulation of osteoclast differentiation and function. J. Bone Miner. Res. 28, 2392–2399. https://doi.org/10.1002/jbmr.1976 (2013). (PMID: 10.1002/jbmr.197623661628)
Yoshizaki, T. et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 298, E419–E428. https://doi.org/10.1152/ajpendo.00417.2009 (2010). (PMID: 10.1152/ajpendo.00417.200919996381)
Lacey, D. L. et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am. J. Pathol. 157, 435–448 (2000). (PMID: 10.1016/S0002-9440(10)64556-7)
Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 19, 107–120. https://doi.org/10.1038/cdd.2011.96 (2012). (PMID: 10.1038/cdd.2011.9621760595)
Shamas-Din, A., Brahmbhatt, H., Leber, B. & Andrews, D. W. BH3-only proteins: orchestrators of apoptosis. Biochim. Biophys. Acta 1813, 508–520. https://doi.org/10.1016/j.bbamcr.2010.11.024 (2011). (PMID: 10.1016/j.bbamcr.2010.11.02421146563)
Dewson, G. et al. Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ. 19, 661–670. https://doi.org/10.1038/cdd.2011.138 (2012). (PMID: 10.1038/cdd.2011.13822015607)
Bock, F. J. & Tait, S. W. G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-019-0173-8 (2019). (PMID: 10.1038/s41580-019-0173-831636403)
Kovacic, N. et al. Fas receptor is required for estrogen deficiency-induced bone loss in mice. Lab. Invest. 90, 402–413. https://doi.org/10.1038/labinvest.2009.144 (2010). (PMID: 10.1038/labinvest.2009.144200840562829329)
Krum, S. A. et al. Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO J. 27, 535–545 (2008). (PMID: 10.1038/sj.emboj.7601984)
Saintier, D. et al. Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro. J. Steroid Biochem. Mol. Biol. 99, 165–173 (2006). (PMID: 10.1016/j.jsbmb.2006.01.009)
Park, H. et al. Interaction of Fas ligand and Fas expressed on osteoclast precursors increases osteoclastogenesis. J. Immunol. 175, 7193–7201 (2005). (PMID: 10.4049/jimmunol.175.11.7193)
Kovacic, N. et al. The Fas/Fas ligand system inhibits differentiation of murine osteoblasts but has a limited role in osteoblast and osteoclast apoptosis. J. Immunol. 178, 3379–3389 (2007). (PMID: 10.4049/jimmunol.178.6.3379)
Wang, L. et al. Osteoblast-induced osteoclast apoptosis by FAS ligand/FAS pathway is required for maintenance of bone mass. Cell Death Differ. 22, 1654–1664. https://doi.org/10.1038/cdd.2015.14 (2015). (PMID: 10.1038/cdd.2015.14257440244563780)
Kousteni, S. et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719–730 (2001). (PMID: 11257226)
Martin-Millan, M. et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol. Endocrinol. 24, 323–334. https://doi.org/10.1210/me.2009-0354 (2010). (PMID: 10.1210/me.2009-0354200537162817608)
Jilka, R. L., Weinstein, R. S., Bellido, T., Parfitt, A. M. & Manolagas, S. C. Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J. Bone Miner. Res. 13, 793–802 (1998). (PMID: 10.1359/jbmr.1998.13.5.793)
Kawakami, A. et al. Fas and Fas ligand interaction is necessary for human osteoblast apoptosis. J. Bone Miner. Res. 12, 1637–1646 (1997). (PMID: 10.1359/jbmr.1997.12.10.1637)
Kawakami, A. et al. Insulin-like growth factor I stimulates proliferation and Fas-mediated apoptosis of human osteoblasts. Biochem. Biophys. Res. Commun. 247, 46–51 (1998). (PMID: 10.1006/bbrc.1998.8728)
Kogianni, G. et al. Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci. 75, 2879–2895 (2004). (PMID: 10.1016/j.lfs.2004.04.048)
Duque, G., El Abdaimi, K., Henderson, J. E., Lomri, A. & Kremer, R. Vitamin D inhibits Fas ligand-induced apoptosis in human osteoblasts by regulating components of both the mitochondrial and Fas-related pathways. Bone 35, 57–64 (2004). (PMID: 10.1016/j.bone.2004.03.005)
Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999). (PMID: 10.1023/A:1008942828960)
Takeuchi, O. et al. Essential role of BAX, BAK in B cell homeostasis and prevention of autoimmune disease. Proc. Natl. Acad. Sci. U.S.A. 102, 11272–11277. https://doi.org/10.1073/pnas.0504783102 (2005). (PMID: 10.1073/pnas.0504783102160555541183578)
Bartell, S. M. et al. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H 2 O 2 accumulation. Nat. Commun. 5, 3773. https://doi.org/10.1038/ncomms4773 (2014). (PMID: 10.1038/ncomms4773247810124015330)
Wang, L. et al. Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo. J. Biol. Chem. 293, 9248–9264. https://doi.org/10.1074/jbc.RA117.000834 (2018). (PMID: 10.1074/jbc.RA117.000834297248256005439)
Krager, K. J. et al. Tocotrienol-rich fraction from rice bran demonstrates potent radiation protection activity. Evid. Based Complement. Alternat. Med. 2015, 148791. https://doi.org/10.1155/2015/148791 (2015). (PMID: 10.1155/2015/148791264251294573888)
Almeida, M., Han, L., Bellido, T., Manolagas, S. C. & Kousteni, S. Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J. Biol. Chem. 280, 41342–41351 (2005). (PMID: 10.1074/jbc.M502168200)
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2 method. Methods 25, 402–408 (2001). (PMID: 10.1006/meth.2001.1262)
Du, P., Kibbe, W. A. & Lin, S. M. Lumi: a pipeline for processing illumina microarray. Bioinformatics 24, 1547–1548. https://doi.org/10.1093/bioinformatics/btn224 (2008). (PMID: 10.1093/bioinformatics/btn224)
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47. https://doi.org/10.1093/nar/gkv007 (2015). (PMID: 10.1093/nar/gkv00744025104402510)
Varemo, L., Nielsen, J. & Nookaew, I. Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods. Nucleic Acids Res. 41, 4378–4391. https://doi.org/10.1093/nar/gkt111 (2013). (PMID: 10.1093/nar/gkt111234441433632109)
Plotkin, L. I. et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J. Clin. Invest. 104, 1363–1374 (1999). (PMID: 10.1172/JCI6800)
Iyer, S. et al. Sirtuin1 (Sirt1) promotes cortical bone formation by preventing β-catenin sequestration by FoxO transcription factors in osteoblast progenitors. J. Biol. Chem. 289, 24069–24078 (2014). (PMID: 10.1074/jbc.M114.561803)
Makinen, M. W. & Lee, C. P. Biochemical studies of skeletal muscle mitochondria. I. Microanalysis of cytochrome content, oxidative and phosphorylative activities of mammalian skeletal muscle mitochondria. Arch Biochem. Biophys. 126, 75–82. https://doi.org/10.1016/0003-9861(68)90561-4 (1968). (PMID: 10.1016/0003-9861(68)90561-44970348)
Ramalho, A. C. et al. Estradiol and raloxifene decrease the formation of multinucleate cells in human bone marrow cultures. Eur. Cytokine Netw. 13, 39–45 (2002). (PMID: 11956019)
Garcia Palacios, V. et al. Negative regulation of RANKL-induced osteoclastic differentiation in RAW264.7 cells by estrogen and phytoestrogens. J. Biol. Chem. 280, 13720–13727. https://doi.org/10.1074/jbc.M410995200 (2005). (PMID: 10.1074/jbc.M41099520015644335)
Sorensen, M. G., Henriksen, K., Dziegiel, M. H., Tanko, L. B. & Karsdal, M. A. Estrogen directly attenuates human osteoclastogenesis, but has no effect on resorption by mature osteoclasts. DNA Cell Biol. 25, 475–483. https://doi.org/10.1089/dna.2006.25.475 (2006). (PMID: 10.1089/dna.2006.25.47516907645)
Wu, X., McKenna, M. A., Feng, X., Nagy, T. R. & McDonald, J. M. Osteoclast apoptosis: the role of Fas in vivo and in vitro. Endocrinology 144, 5545–5555 (2003). (PMID: 10.1210/en.2003-0296)
Bartell, S. M. et al. Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. Mol. Endocrinol. 27, 649–656. https://doi.org/10.1210/me.2012-1368 (2013). (PMID: 10.1210/me.2012-1368234432673607700)
Almeida, M. et al. Estrogen receptor-alpha signaling in osteoblast progenitors stimulates cortical bone accrual. J. Clin. Invest. 123, 394–404. https://doi.org/10.1172/JCI65910 (2013). (PMID: 10.1172/JCI6591023221342)
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U.S.A. 102, 15545–15550. https://doi.org/10.1073/pnas.0506580102 (2005). (PMID: 10.1073/pnas.0506580102161995171239896)
Wirth, C., Brandt, U., Hunte, C. & Zickermann, V. Structure and function of mitochondrial complex I. Biochim. Biophys. Acta 1857, 902–914. https://doi.org/10.1016/j.bbabio.2016.02.013 (2016). (PMID: 10.1016/j.bbabio.2016.02.01326921811)
Bae, S. et al. MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRalpha. J. Clin. Invest. 127, 2555–2568. https://doi.org/10.1172/JCI89935 (2017). (PMID: 10.1172/JCI89935285306455490751)
Schagger, H. & von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223–231. https://doi.org/10.1016/0003-2697(91)90094-a (1991). (PMID: 10.1016/0003-2697(91)90094-a1812789)
Zeng, R., Faccio, R. & Novack, D. V. Alternative NF-κB regulates RANKL-induced osteoclast differentiation and mitochondrial biogenesis via independent mechanisms. J. Bone Miner. Res. 30, 2287–2299. https://doi.org/10.1002/jbmr.2584 (2015). (PMID: 10.1002/jbmr.2584260948464834842)
Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629. https://doi.org/10.1126/science.1099320 (2004). (PMID: 10.1126/science.109932015286356)
Jilka, R. L. et al. Dysapoptosis of osteoblasts and osteocytes increases cancellous bone formation but exaggerates cortical porosity with age. J. Bone Miner. Res. 29, 103–117. https://doi.org/10.1002/jbmr.2007 (2014). (PMID: 10.1002/jbmr.200723761243)
Roths, J. B., Murphy, E. D. & Eicher, E. M. A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J. Exp. Med. 159, 1–20. https://doi.org/10.1084/jem.159.1.1 (1984). (PMID: 10.1084/jem.159.1.16693832)
Andrews, B. S. et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J. Exp. Med. 148, 1198–1215. https://doi.org/10.1084/jem.148.5.1198 (1978). (PMID: 10.1084/jem.148.5.1198309911)
Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317. https://doi.org/10.1038/356314a0 (1992). (PMID: 10.1038/356314a01372394)
Kim, H. N. et al. Sirtuin1 suppresses osteoclastogenesis by deacetylating FoxOs. Mol. Endocrinol. 29, 1498–1509. https://doi.org/10.1210/me.2015-1133 (2015). (PMID: 10.1210/me.2015-1133262875184588729)
Hirst, J. Mitochondrial complex I. Annu. Rev. Biochem. 82, 551–575. https://doi.org/10.1146/annurev-biochem-070511-103700 (2013). (PMID: 10.1146/annurev-biochem-070511-10370023527692)
de Otamendi, M. E. & Stoppani, A. O. Action of diethylstilbestrol on the NADH-dehydrogenase region of the respiratory chain. Arch. Biochem. Biophys. 165, 21–33 (1974). (PMID: 10.1016/0003-9861(74)90137-4)
Felty, Q. & Roy, D. Estrogen, mitochondria, and growth of cancer and non-cancer cells. J. Carcinog. 4, 1. https://doi.org/10.1186/1477-3163-4-1 (2005). (PMID: 10.1186/1477-3163-4-115651993548143)
Moreira, P. I., Custodio, J., Moreno, A., Oliveira, C. R. & Santos, M. S. Tamoxifen and estradiol interact with the flavin mononucleotide site of complex I leading to mitochondrial failure. J. Biol. Chem. 281, 10143–10152. https://doi.org/10.1074/jbc.M510249200 (2006). (PMID: 10.1074/jbc.M51024920016410252)
Jin, Z., Wei, W., Yang, M., Du, Y. & Wan, Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab. 20, 483–498. https://doi.org/10.1016/j.cmet.2014.07.011 (2014). (PMID: 10.1016/j.cmet.2014.07.011251303994156549)
Karamanlidis, G. et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239–250. https://doi.org/10.1016/j.cmet.2013.07.002 (2013). (PMID: 10.1016/j.cmet.2013.07.002239317553779647)
Kruse, S. E. et al. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 7, 312–320. https://doi.org/10.1016/j.cmet.2008.02.004 (2008). (PMID: 10.1016/j.cmet.2008.02.004183961372593686)
Simpkins, J. W., Yi, K. D., Yang, S. H. & Dykens, J. A. Mitochondrial mechanisms of estrogen neuroprotection. Biochim. Biophys. Acta 1800, 1113–1120. https://doi.org/10.1016/j.bbagen.2009.11.013 (2010). (PMID: 10.1016/j.bbagen.2009.11.01319931595)
Stirone, C., Duckles, S. P., Krause, D. N. & Procaccio, V. Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. Mol. Pharmacol. 68, 959–965. https://doi.org/10.1124/mol.105.014662 (2005). (PMID: 10.1124/mol.105.01466215994367)
Arnold, S., Victor, M. B. & Beyer, C. Estrogen and the regulation of mitochondrial structure and function in the brain. J. Steroid Biochem. Mol. Biol. 131, 2–9. https://doi.org/10.1016/j.jsbmb.2012.01.012 (2012). (PMID: 10.1016/j.jsbmb.2012.01.01222326731)
Ribas, V. et al. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci. Transl. Med. 8, 334–354. https://doi.org/10.1126/scitranslmed.aad3815 (2016). (PMID: 10.1126/scitranslmed.aad3815)
Zhou, Z. et al. Estrogen receptor alpha protects pancreatic beta-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J. Biol. Chem. 293, 4735–4751. https://doi.org/10.1074/jbc.M117.805069 (2018). (PMID: 10.1074/jbc.M117.805069293788455880140)
Chen, J. Q., Yager, J. D. & Russo, J. Regulation of mitochondrial respiratory chain structure and function by estrogens/estrogen receptors and potential physiological/pathophysiological implications. Biochim. Biophys. Acta 1746, 1–17. https://doi.org/10.1016/j.bbamcr.2005.08.001 (2005). (PMID: 10.1016/j.bbamcr.2005.08.00116169101)
Levin, E. R. Extranuclear steroid receptors are essential for steroid hormone actions. Annu. Rev. Med. 66, 271–280. https://doi.org/10.1146/annurev-med-050913-021703 (2015). (PMID: 10.1146/annurev-med-050913-02170325587652)
Kwak, H. B. et al. Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression. Bone 46, 724–731. https://doi.org/10.1016/j.bone.2009.10.042 (2010). (PMID: 10.1016/j.bone.2009.10.04219900598)
Kim, J. M. et al. Osteoclast precursors display dynamic metabolic shifts toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation. Cell Physiol. Biochem. 20, 935–946. https://doi.org/10.1159/000110454 (2007). (PMID: 10.1159/00011045417982276)
Miyazaki, T. et al. Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption. J. Biol. Chem. 287, 37808–37823. https://doi.org/10.1074/jbc.M112.385369 (2012). (PMID: 10.1074/jbc.M112.385369229882533488055)
Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751 (2005). (PMID: 10.1146/annurev.genet.39.110304.095751162858652821041)
Garrett, I. R. et al. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J. Clin. Invest. 85, 632–639 (1990). (PMID: 10.1172/JCI114485)
Levasseur, R. et al. Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice. Endocrinology 144, 2761–2764 (2003). (PMID: 10.1210/en.2002-0071)
Bai, X. C. et al. Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J. Biol. Chem. 280, 17497–17506 (2005). (PMID: 10.1074/jbc.M409332200)
Lean, J. M., Jagger, C. J., Kirstein, B., Fuller, K. & Chambers, T. J. Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. Endocrinology 146, 728–735 (2005). (PMID: 10.1210/en.2004-1021)
Lee, N. K. et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106, 852–859 (2005). (PMID: 10.1182/blood-2004-09-3662)
Ucer, S. et al. The effects of aging and sex steroid deficiency on the murine skeleton are independent and mechanistically distinct. J. Bone Miner. Res. 32, 560–574. https://doi.org/10.1002/jbmr.3014 (2017). (PMID: 10.1002/jbmr.301427714847)
Grant Information:: P20 GM125503 United States GM NIGMS NIH HHS; R01 AR056679 United States AR NIAMS NIH HHS; 1UL1RR029884 United States NH NIH HHS; P01 AG013918 United States AG NIA NIH HHS; P01 AG013918 United States NH NIH HHS; P20 GM125503 United States NH NIH HHS; P20 GM109005 United States GM NIGMS NIH HHS; P20 GM109005 United States NH NIH HHS; UL1 RR029884 United States RR NCRR NIH HHS; I01 BX001405 United States BX BLRD VA; R01 AR056679 United States NH NIH HHS; Intramural grant United States AG NIA NIH HHS
Substance Nomenclature:: 0 (Biomarkers)
0 (Estrogens)
8L70Q75FXE (Adenosine Triphosphate)
Entry Date(s):: Date Created: 20200721 Date Completed: 20201221 Latest Revision: 20210720
Update Code:: 20240104
PubMed Central ID:: PMC7371870
DOI:: 10.1038/s41598-020-68890-7
PMID:: 32686739
: Czasopismo naukowe

Pełny tekst

Loss of estrogens at menopause is a major cause of osteoporosis and increased fracture risk. Estrogens protect against bone loss by decreasing osteoclast number through direct actions on cells of the myeloid lineage. Here, we investigated the molecular mechanism of this effect. We report that 17β-estradiol (E 2 ) decreased osteoclast number by promoting the apoptosis of early osteoclast progenitors, but not mature osteoclasts. This effect was abrogated in cells lacking Bak/Bax-two pro-apoptotic members of the Bcl-2 family of proteins required for mitochondrial apoptotic death. FasL has been previously implicated in the pro-apoptotic actions of E 2 . However, we show herein that FasL-deficient mice lose bone mass following ovariectomy indistinguishably from FasL-intact controls, indicating that FasL is not a major contributor to the anti-osteoclastogenic actions of estrogens. Instead, using microarray analysis we have elucidated that ERα-mediated estrogen signaling in osteoclast progenitors decreases "oxidative phosphorylation" and the expression of mitochondria complex I genes. Additionally, E 2 decreased the activity of complex I and oxygen consumption rate. Similar to E 2 , the complex I inhibitor Rotenone decreased osteoclastogenesis by promoting osteoclast progenitor apoptosis via Bak/Bax. These findings demonstrate that estrogens decrease osteoclast number by attenuating respiration, and thereby, promoting mitochondrial apoptotic death of early osteoclast progenitors.

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