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The Estrogen Receptor-α in Osteoclasts Mediates the Protective Effects of Estrogens on Cancellous But Not Cortical Bone
Open accessAbstract
Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)α from the monocyte/macrophage cell lineage in mice (ERαLysM−/−) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERαLysM−/− were resistant to the proapoptotic effect of 17β-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERα knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERα was as effective as 17β-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERα. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERα. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton.
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“Moreover, it has been shown that osteoclast is a direct target for estrogen [163, 164].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [164]
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Metadata
- Authors
- Martin-Millan, M., Almeida, M., Ambrogini, E., Han, L., Zhao, H., Weinstein, R. S., Jilka, R. L., O'Brien, C. A., & Manolagas, S. C.
- Affiliations
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205
- Central Arkansas Veterans Healthcare System (US)
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2010-02-01
- Volume
- 24
- Issue
- 2
- Pages
- 323-334
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2817608
- OpenAlex
- W2081379880
- Cited by
- 282
- References
- 65
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 12 · 2023: 22 · 2022: 22 · 2021: 13 · 2020: 25 · 2019: 14 · 2018: 15 · 2017: 18 · 2016: 19 · 2015: 18 · 2014: 21 · 2013: 19 · 2012: 16
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01 AG-13918, P01AG013918)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR49794, R01AR049794)
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- estrogen receptor alpha, osteoclasts, estrogen, trabecular bone, cortical bone, osteoclastogenesis, osteoclast apoptosis, estradiol, monocyte/macrophage lineage, bone loss, osteoporosis, osteoblasts, osteocytes
- MeSH terms
- Animals, Bone and Bones, Bone Marrow Cells, Bone Resorption, Cells, Cultured, Chimera, Estradiol, Estrogens, Female, Macrophages, Organ Specificity, Osteoblasts, Osteoclasts, Osteoporosis, Ovariectomy, RNA, Messenger, Bone Density, Apoptosis, Gene Targeting, Estrogen Receptor alpha, Mice, Gene Knock-In Techniques
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