Cited by 813Bone Metabolism and DiseasesEstrogen and related hormone effectsBone health and osteoporosis research

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Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β

Hughes, Davis E., Dai, Aihua, Tiffee, John C., Li, He Hiu, Mundy, Gregory R., Boyce, Brendan F.·1996·Nature Medicine

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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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Self-citation
Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo
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Background
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Background
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BackgroundInfluential
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Background
Preventing Bone Loss and Weight Gain with Combinations of Vitamin D and Phytochemicals
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Background
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“An interesting finding in relation to the osteoclast phenotype in the ADOI patients is the increased level of transforming growth factor,(37) which has been shown to inhibit osteoclast maturation and thereby function,(26) and induce apoptosis.(42) This finding correlates well with the lower number of small osteoclasts…”
Result
Estrogen Directly Attenuates Human Osteoclastogenesis, But Has No Effect on Resorption by Mature Osteoclasts
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Background
Low-dose combined oral contraceptive use is associated with lower bone mineral content variation in adolescents over a 1-year period
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Background
Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca2+ Signaling Pathway and Prevents Inflammation-Mediated Bone Loss
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Background
Inhibition of osteoclastogenesis by mechanically stimulated osteoblasts is attenuated during estrogen deficiency
Allison, H., & McNamara, L. M. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00168.2019 · Cited by 41
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“However, different from the effect of estrogen on the regulation of apoptosis [38,69,184], clinical and cell culture studies indicate that raloxifene neither enhances the osteoclast apoptosis [185] nor suppress osteocyte apoptosis [186], except that raloxifene could protect osteoblast from apoptosis induced by sodium…”
Background
Transient estrogen exposure of female mice during early development permanently affects osteoclastogenesis in adulthood
Migliaccio, S., Newbold, R. R., Teti, A. M., Jefferson, W. N., Toverud, S. U., Taranta, A., Bullock, B. C., Suggs, C., Spera, G., & Korach, K. S. (2000) · Bone · doi:10.1016/s8756-3282(00)00286-6 · Cited by 41
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Identification of Estrogen-Regulated Genes of Potential Importance for the Regulation of Trabecular Bone Mineral Density
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“Another pathway, by which estrogen has been suggested to exert its bone-protective effects, is via increased expression of TGF- .((17,19,38)) TGF- induces apoptosis of osteoclasts, resulting in decreased bone resorption.”
Background
Osteoporosis: Current approaches and future prospects in diagnosis, pathogenesis, and management
Raisz, L. G. (1999) · Journal of Bone and Mineral Metabolism · doi:10.1007/s007740050069 · Cited by 41
“Estrogen can increase programmed cell death or apoptosis in cell cultures of osteoclasts, and this effect can be mimicked by selective estrogen receptor modulators such as tamoxifen and also by TGF-â [62].”
BackgroundInfluential
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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
Publisher: Springer Science and Business Media LLC
Published: 1996-10
Volume: 2
Issue: 10
Pages: 1132-1136
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm1096-1132
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 › Endocrinology › 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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Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β

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