Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β
Abstract
Postmenopausal osteoporosis, the most common bone disease in the developed world, is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perforate bone trabeculae, thus reducing their strength and increasing fracture risk. Estrogen replacement prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life span and thus the amount of bone that osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis. 17 beta-Estradiol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone resorption, and transforming growth factor-beta 1 (TGF-beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogues to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.
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Estrogen suppresses osteoclast formation and activity.
“The estrogen suppresses the osteoclast formation and activity as well as induces osteoclast apoptosis [16, 76, 104, 154].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [154]
Estrogen induces osteoclast apoptosis.
“The estrogen suppresses the osteoclast formation and activity as well as induces osteoclast apoptosis [16, 76, 104, 154].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [154]
Estrogen can increase TGF-β and OPG levels, which inhibit osteoclast differentiation.
“In addition, estrogen can also increase TGF-β and osteoprotegerin (OPG) levels, which inhibit osteoclast differentiation [[58], [59], [60]].”
From Emerging role of liver-bone axis in osteoporosis (2024) · cites this paper as [60]
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Self-citation
- Authors
- Hughes, D. E., Dai, A., Tiffee, J. C., Li, H. H., Mundy, G. R., & Boyce, B. F.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- ORCID
- Boyce, Brendan F.
- Venue
- Nature Medicine
- Published
- 1996-10
- Volume
- 2
- Issue
- 10
- Pages
- 1132-1136
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2016674232
- Cited by
- 813
- References
- 27
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 13 · 2023: 20 · 2022: 23 · 2021: 24 · 2020: 23 · 2019: 22 · 2018: 22 · 2017: 15 · 2016: 22 · 2015: 27 · 2014: 16 · 2013: 29 · 2012: 27
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ar039529-07)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 45299)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 43510, AR 39529, R01AR043510)
- 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 › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- estrogen, osteoclast apoptosis, TGF-beta, postmenopausal osteoporosis, estradiol, tamoxifen, bone resorption, estrogen deficiency, anti-TGF-beta antibody, estrogen replacement therapy, bone loss prevention
- MeSH terms
- Animals, Bone and Bones, Bone Resorption, Cell Count, Cells, Cultured, Estradiol, Estrogen Antagonists, Female, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Organ Size, Osteoblasts, Osteoclasts, Ovariectomy, Tamoxifen, Uterus, Osteoporosis, Postmenopausal, Transforming Growth Factor beta, Apoptosis, Mice
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