Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-α with BCAR1 and Traf6
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The effects of estrogen on osteoclast survival and differentiation were studied using CD14-selected mononuclear osteoclast precursors from peripheral blood. Estradiol at approximately 1 nM reduced RANKL-dependent osteoclast differentiation by 40-50%. Osteoclast differentiation was suppressed 14 days after addition of RANKL even when estradiol was withdrawn after 18 h. In CD14+ cells apoptosis was rare and was not augmented by RANKL or by 17-beta-estradiol. Estrogen receptor-alpha (ERalpha) expression was strongly down-regulated by RANKL, whether or not estradiol was present. Mature human osteoclasts thus cannot respond to estrogen via ERalpha. However, ERalpha was present in CD14+ osteoclast progenitors, and a scaffolding protein, BCAR1, which binds ERalpha in the presence of estrogen, was abundant. Immunoprecipitation showed rapid (approximately 5 min) estrogen-dependent formation of ERalpha-BCAR1 complexes, which were increased by RANKL co-treatment. The RANKL-signaling intermediate Traf6, which regulates NF-kappaB activity, precipitated with this complex. Reduction of NF-kappaB nuclear localization occurred within 30 min of RANKL stimulation, and estradiol inhibited the phosphorylation of IkappaB in response to RANKL. Inhibition by estradiol was abolished by siRNA knockdown of BCAR1. We conclude that estrogen directly, but only partially, curtails human osteoclast formation. This effect requires BCAR1 and involves a non-genomic interaction with ERalpha.
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Estrogen stimulates osteoblasts and osteocytes to produce osteoprotegerin (OPG), which inhibits osteoclastogenesis.
“Moreover, estrogen stimulates these bone cells to produce osteoprotegerin (OPG), a decoy receptor of RANK in osteoclast, thus inhibiting osteoclastogenesis [19, 155–159].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [159]
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- Authors
- Robinson, L. J., Yaroslavskiy, B. B., Griswold, R. D., Zadorozny, E. V., Guo, L., Tourkova, I. L., & Blair, H. C.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Robinson, Lisa J.
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 315
- Issue
- 7
- Pages
- 1287-1301
- ISSN
- 0014-4827 (ISSN-L)
- PMC
- PMC2765696
- OpenAlex
- W1992438132
- Cited by
- 95
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 6 · 2014: 4 · 2013: 8 · 2012: 7
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AR053566, AR47700)
- U.S. Department of Veterans Affairs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- estrogen, estradiol, RANKL, osteoclastogenesis, estrogen receptor alpha, p130Cas, TRAF6, monocytes, non-genomic estrogen signaling, NF-κB, IκB phosphorylation, osteoclast precursors, apoptosis
- MeSH terms
- Animals, Cell Differentiation, Cell Survival, Cells, Cultured, Estrogens, Female, Humans, Monocytes, Osteoclasts, Signal Transduction, NF-kappa B, Lipopolysaccharide Receptors, RNA, Small Interfering, Estrogen Receptor alpha, TNF Receptor-Associated Factor 6, Crk-Associated Substrate Protein, RANK Ligand
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