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

Sci Rep. 2020 Jul 20;10(1):11933. doi: 10.1038/s41598-020-68890-7.


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 (E2) 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 E2. 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, E2 decreased the activity of complex I and oxygen consumption rate. Similar to E2, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • 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 / metabolism*
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Monocyte-Macrophage Precursor Cells / cytology
  • Monocyte-Macrophage Precursor Cells / drug effects
  • Monocyte-Macrophage Precursor Cells / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis / drug effects
  • Oxidative Phosphorylation*
  • Signal Transduction


  • Biomarkers
  • Estrogens
  • Adenosine Triphosphate