Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice
Open accessAbstract
The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bone-sparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα flox/flox mice to generate mice lacking ERα protein expression specifically in osteocytes ( Dmp1-ERα −/− ). Male Dmp1-ERα −/− mice displayed a substantial reduction in trabecular bone volume (−20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (−45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα −/− mice. The male Dmp1-ERα −/− mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2 , Sp7 , and Dmp1 ( P < 0.05). Gonadal intact Dmp1-ERα −/− female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα −/− female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα −/− mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.
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Several additional cell specific ERα KO mice have been generated including osteocytes and hepatocytes that show no change in fat phenotype.
“Several additional cell specific ERα KO mice have been generated including osteocytes 211 and hepatocytes 212 that show no change in fat phenotype.”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [211]
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- Authors
- Windahl, S. H., Börjesson, A. E., Farman, H. H., Engdahl, C., Movérare-Skrtic, S., Sjögren, K., Lagerquist, M. K., Kindblom, J. M., Koskela, A., Tuukkanen, J., Divieti Pajevic, P., Feng, J. Q., Dahlman-Wright, K., Antonson, P., Gustafsson, J.-Å., & Ohlsson, C.
- Affiliations
- University of Gothenburg (SE)
- Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;
- University of Oulu (FI)
- Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114;
- Texas A&M Health Science Center (US)
- Department of Biosciences and Nutrition and Center for Biosciences at Novum, Karolinska Institutet, 141 83 Huddinge, Sweden; and
- Karolinska Institutet (SE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-01-23
- Volume
- 110
- Issue
- 6
- Pages
- 2294-2299
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3568324
- OpenAlex
- W2016772743
- Cited by
- 136
- References
- 38
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 12 · 2020: 10 · 2019: 18 · 2018: 2 · 2017: 11 · 2016: 13 · 2015: 22 · 2014: 8 · 2013: 6
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation ((E-0004))
- Stiftelsen för Strategisk Forskning
- Novo Nordisk
- Vetenskapsrådet (E-0004)
- Novo Nordisk Fonden (NNF13OC0005785)
- National Institutes of Health (DK071122)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK071122, R01DK071122, DK-071122)
- 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 receptor alpha, osteocytes, trabecular bone formation, trabecular bone volume, cortical bone, ovariectomy, sex differences in bone, osteoblast markers, Runx2, Osterix, DMP1, osteoclasts
- MeSH terms
- Animals, Bone and Bones, Bone Development, Bone Resorption, Cell Count, Estradiol, Female, Male, Mice, Transgenic, Osteoclasts, Osteocytes, Osteogenesis, Ovariectomy, Ovary, Sex Characteristics, Stress, Mechanical, Bone Remodeling, Mice, Knockout, Estrogen Receptor alpha, Mice
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