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

Area of Science:

• Endocrinology
• Bone Biology
• Cellular Biology

Background:

• Menopause-associated estrogen loss accelerates osteoporosis and fracture risk.
• Estrogens normally inhibit bone resorption by reducing osteoclast numbers.
• The precise molecular mechanisms underlying estrogen's anti-osteoclastogenic effects require elucidation.

Purpose of the Study:

• To investigate the molecular mechanism by which 17β-estradiol (E2) reduces osteoclast number.
• To determine if FasL mediates the anti-osteoclastogenic effects of E2.
• To identify the cellular pathways involved in E2-induced osteoclast progenitor apoptosis.

Main Methods:

• Utilized ovariectomized mouse models and isolated osteoclast progenitors.
• Assessed apoptosis via Bak/Bax and mitochondrial pathways.
• Performed microarray analysis to identify gene expression changes.
• Measured mitochondrial complex I activity and oxygen consumption rates.

Main Results:

• E2 induced apoptosis in early osteoclast progenitors, not mature osteoclasts, dependent on Bak/Bax.
• FasL-deficient mice exhibited bone loss similar to controls, indicating FasL is not critical.
• E2 signaling via ERα downregulated oxidative phosphorylation and mitochondrial complex I gene expression.
• E2 inhibited complex I activity and oxygen consumption; Rotenone mimicked E2's effects.

Conclusions:

• Estrogens decrease osteoclast number by promoting apoptosis in osteoclast progenitors.
• This effect is mediated by E2-induced attenuation of mitochondrial respiration and complex I activity.
• Estrogen's protective role against bone loss involves regulating progenitor cell bioenergetics via ERα.