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

Autor:	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. schullermaria@uams.edu.; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, USA. schullermaria@uams.edu.; Central Arkansas Veterans Healthcare System, Little Rock, AR, 72205, USA. schullermaria@uams.edu.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2020 Jul 20; Vol. 10 (1), pp. 11933. Date of Electronic Publication: 2020 Jul 20.
DOI:	10.1038/s41598-020-68890-7
Abstrakt:	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.
Databáze:	MEDLINE
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