Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids
Abstract
We show that sex steroids protect the adult murine skeleton through a mechanism that is distinct from that used to preserve the mass and function of reproductive organs. The classical genotropic actions of sex steroid receptors are dispensable for their bone protective effects, but essential for their effects on reproductive tissues. A synthetic ligand (4-estren-3α,17β-diol) that reproduces the nongenotropic effects of sex steroids, without affecting classical transcription, increases bone mass and strength in ovariectomized females above the level of the estrogen-replete state and is at least as effective as dihydrotestosterone in orchidectomized males, without affecting reproductive organs. Such ligands merit investigation as potential therapeutic alternatives to hormone replacement for osteoporosis of bone mass in both women and men.
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Estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis.
“Nevertheless, several studies have shown that estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis [151–153] and preventing excessive bone resorption.”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [152]
Estrogen prevents excessive bone resorption.
“Nevertheless, several studies have shown that estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis [151–153] and preventing excessive bone resorption.”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [152]
Osteocyte apoptosis acts as a chemotactic signal for local osteoclast recruitment.
“Osteocyte apoptosis has been shown to act as a chemotactic signal for local osteoclast recruitment [70, 150, 152, 190, 191].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [152]
Cites
Writing Group for the Women's Health Initiative Investigators (2002) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.288.3.321 · Cited by 15,889 · see citing works
Manolagas, S. C. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.2.0395 · Cited by 2,575 · see citing works
Self-citationSex Steroids and the Construction and Conservation of the Adult Skeleton
Riggs, B. L., Khosla, S., & Melton, L. J. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.3.0465 · Cited by 1,846 · see citing works
High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5
Boyden, L. M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M. A., Wu, D., Insogna, K., & Lifton, R. P. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa013444 · Cited by 1,591 · see citing works
Estrogen Actions in the Central Nervous System
McEwen, B. S., & Alves, S. E. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.3.0365 · Cited by 1,483 · see citing works
Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators
McKenna, N. J., & O'Malley, B. W. (2002) · Cell · doi:10.1016/s0092-8674(02)00641-4 · Cited by 1,463 · see citing works
Gebbie, A. E. (2002) · Journal of Family Planning and Reproductive Health Care · doi:10.1783/147118902101196685 · Cited by 1,178 · see citing works
Nongenotropic, Sex-Nonspecific Signaling through the Estrogen or Androgen Receptors
Kousteni, S., Bellido, T., Plotkin, L. I., O’Brien, C. A., Bodenner, D., Li, H., Han, K., Gregorio, G. B. D., Katzenellenbogen, J. A., Katzenellenbogen, B. S., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00268-9 · Cited by 1,163 · see citing works
Self-citationDNA binding of the glucocorticoid receptor is not essential for survival
Reichardt, H. M., Kaestner, K. H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81183-6 · Cited by 1,068 · see citing works
Multiple Actions of Steroid Hormones—A Focus on Rapid, Nongenomic Effects
Falkenstein, E., Tillmann, H.-C., Christ, M., Feuring, M., & Wehling, M. (2000) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01468-6 · Cited by 986 · see citing works
Estrogen receptor pathways to AP-1.
Kushner, P., Agard, D., Greene, G., Scanlan, T., Shiau, A., Uht, R., & Webb, P. (2000) · Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(00)00108-4 · Cited by 953 · see citing works
Chen, Z., Yuhanna, I. S., Galcheva-Gargova, Z., Karas, R. H., Mendelsohn, M. E., & Shaul, P. W. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5347 · Cited by 924 · see citing works
Manolagas, S. C. (2002) · Recent Progress in Hormone Research · doi:10.1210/rp.57.1.385 · Cited by 523 · see citing works
Self-citationHormone Replacement Therapy and Cardiovascular Disease
Mosca, L. J., Collins, P. D., Herrington, D. M., Mendelsohn, M. E., Pasternak, R. C., Robertson, R. M., Schenck-Gustafsson, K. G., Smith, S. C., Taubert, K. A., & WENGER, N. K. (2001) · Circulation · doi:10.1161/hc2901.092200 · Cited by 437 · see citing works
Estrogen receptors: orchestrators of pleiotropic cellular responses
Moggs, J. G., & Orphanides, G. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve185 · Cited by 234 · see citing works
Grotewold, L., & Rüther, U. (2002) · The EMBO Journal · doi:10.1093/emboj/21.5.966 · Cited by 199 · see citing works
Fitzpatrick, J. L., Mize, A. L., Wade, C. B., Harris, J. A., Shapiro, R. A., & Dorsa, D. M. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01000.x · Cited by 156 · see citing works
Doran, P. M., Riggs, B. L., Atkinson, E. J., & Khosla, S. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.11.2118 · Cited by 115 · see citing works
Ott, S. M., Oleksik, A., Lu, Y., et al. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.2.341 · Cited by 108 · see citing works
Perspective: Nonreproductive Sites of Action of Reproductive Hormones
Manolagas, S. C., & Kousteni, S. (2001) · Endocrinology · doi:10.1210/endo.142.6.8221 · Cited by 100 · see citing works
Self-citationHigh-Dose Estrogen Induces De Novo Medullary Bone Formation in Female Mice
Samuels, A., Perry, M. J., & Tobias, J. H. (1999) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1999.14.2.178 · Cited by 93 · see citing works
Mechanisms of Estrogen Receptor Action in the Myocardium
de Jager, T., Pelzer, T., Müller-Botz, S., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010984200 · Cited by 87 · see citing works
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Cited by
Sorted by citations
Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells
Florencio-Silva, R., Sasso, G. R. D. S., Sasso-Cerri, E., Simões, M. J., & Cerri, P. S. (2015) · BioMed Research International · doi:10.1155/2015/421746 · Cited by 2,044 · see citing works
Estrogens and androgens in skeletal physiology and pathophysiology
Almeida, M., Laurent, M. R., Dubois, V., Claessens, F., O'Brien, C. A., Bouillon, R., Vanderschueren, D., & Manolagas, S. C. (2017) · Physiological Reviews · doi:10.1152/physrev.00033.2015 · Cited by 860 · see citing works
Self-citationVanderschueren, D., Vandenput, L., Boonen, S., Lindberg, M. K., Bouillon, R., & Ohlsson, C. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0003 · Cited by 717 · see citing works
Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model
Norman, A. W., Mizwicki, M. T., & Norman, D. P. G. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1283 · Cited by 569 · see citing works
Extranuclear Steroid Receptors: Nature and Actions
Hammes, S. R., & Levin, E. R. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0022 · Cited by 475 · see citing works
The Bare Bones of Sex: Part 1—Sex and Gender
Fausto‐Sterling, A. (2005) · Signs: Journal of Women in Culture and Society · doi:10.1086/424932 · Cited by 437 · see citing works
Glucocorticoids Act Directly on Osteoclasts to Increase Their Life Span and Reduce Bone Density
Jia, D., O’Brien, C. A., Stewart, S. A., Manolagas, S. C., & Weinstein, R. S. (2006) · Endocrinology · doi:10.1210/en.2006-0459 · Cited by 394 · see citing works
Self-citationGiant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy
Weinstein, R. S., Roberson, P. K., & Manolagas, S. C. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0802633 · Cited by 391 · see citing works
Self-citationOsteocyte-Driven Bone Remodeling
Bellido, T. (2014) · Calcified Tissue International · doi:10.1007/s00223-013-9774-y · Cited by 384 · see citing works
Self-citationMechanisms of sex steroid effects on bone
Syed, F., & Khosla, S. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.097 · Cited by 380 · see citing works
Sex Steroid Actions in Male Bone
Vanderschueren, D., Laurent, M. R., Claessens, F., Gielen, E., Lagerquist, M. K., Vandenput, L., Börjesson, A. E., & Ohlsson, C. (2014) · Endocrine Reviews · doi:10.1210/er.2014-1024 · Cited by 327 · see citing works
Cenci, S., Toraldo, G., Weitzmann, M. N., Roggia, C., Gao, Y., Qian, W. P., Sierra, O., & Pacifici, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1533207100 · Cited by 309 · see citing works
Martin-Millan, M., Almeida, M., Ambrogini, E., Han, L., Zhao, H., Weinstein, R. S., Jilka, R. L., O'Brien, C. A., & Manolagas, S. C. (2010) · Molecular Endocrinology · doi:10.1210/me.2009-0354 · Cited by 282 · see citing works
Self-citationOsteocytic signalling pathways as therapeutic targets for bone fragility
Plotkin, L. I., & Bellido, T. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.71 · Cited by 206 · see citing works
Self-citationFracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence
Saul, D., & Khosla, S. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac008 · Cited by 185 · see citing works
Mazziotti, G., Frara, S., & Giustina, A. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00005 · Cited by 181 · see citing works
Receptor Mechanisms Mediating Non-Genomic Actions of Sex Steroids
Boonyaratanakornkit, V., & Edwards, D. (2007) · Seminars in Reproductive Medicine · doi:10.1055/s-2007-973427 · Cited by 178 · see citing works
Robinson, L. J., Yaroslavskiy, B. B., Griswold, R. D., Zadorozny, E. V., Guo, L., Tourkova, I. L., & Blair, H. C. (2009) · Experimental Cell Research · doi:10.1016/j.yexcr.2009.01.014 · Cited by 95 · see citing works
Apoptotic Osteocytes and the Control of Targeted Bone Resorption
Plotkin, L. I. (2014) · Current Osteoporosis Reports · doi:10.1007/s11914-014-0194-3 · Cited by 93 · see citing works
Self-citationRecent insights into non-nuclear actions of estrogen receptor alpha
Banerjee, S., Chambliss, K. L., Mineo, C., & Shaul, P. W. (2014) · Steroids · doi:10.1016/j.steroids.2013.11.002 · Cited by 58 · see citing works
Estrogens: Two nuclear receptors, multiple possibilities
Biason-Lauber, A., & Lang-Muritano, M. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111710 · Cited by 49 · see citing works
Almeida, M., Han, L., O’Brien, C. A., Kousteni, S., & Manolagas, S. C. (2006) · Endocrinology · doi:10.1210/en.2005-1314 · Cited by 40 · see citing works
Self-citationPastorelli, R., Carpi, D., Airoldi, L., Chiabrando, C., Bagnati, R., Fanelli, R., Moverare, S., & Ohlsson, C. (2005) · PROTEOMICS · doi:10.1002/pmic.200401325 · Cited by 38 · see citing works
Cruzoé‐Souza, M., Sasso‐Cerri, E., & Cerri, P. S. (2009) · Journal of Anatomy · doi:10.1111/j.1469-7580.2009.01158.x · Cited by 38 · see citing works
- Authors
- Kousteni, S., Chen, J.-R., Bellido, T., Han, L., Ali, A. A., O'Brien, C. A., Plotkin, L., Fu, Q., Mancino, A. T., Wen, Y., Vertino, A. M., Powers, C. C., Stewart, S. A., Ebert, R., Parfitt, A. M., Weinstein, R. S., Jilka, R. L., & Manolagas, S. C.
- Affiliations
- Division of Endocrinology and Metabolism, Department of Internal Medicine, and Center for Osteoporosis and Metabolic Bone Diseases;
- Central Arkansas Veterans Healthcare System (US)
- University of Arkansas for Medical Sciences (US)
- Department of Pathology;
- Corresponding author
- Manolagas, S. C.
- Venue
- Science
- Published
- 2002-10-25
- Volume
- 298
- Issue
- 5594
- Pages
- 843-846
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2144924096
- Cited by
- 420
- References
- 22
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 17 · 2014: 14 · 2013: 19 · 2012: 18
- FWCI
- 20.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P01 AG-13918, P01AG013918)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (KO2-AR-02127, K02AR002127)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- sex steroids, bone loss, osteoporosis, estrogen receptor, androgen receptor, ovariectomy, orchiectomy, bone mass, bone strength, hormone replacement therapy, sex steroid receptors
- MeSH terms
- Animals, Body Weight, Bone and Bones, Breast Neoplasms, Cell Division, Cells, Cultured, Estradiol, Estrenes, Female, Humans, Male, Orchiectomy, Organ Size, Osteoblasts, Osteoclasts, Osteogenesis, Osteoporosis, Ovariectomy, Pyrazoles, Receptors, Estrogen, Seminal Vesicles, Dihydrotestosterone, Transcription, Genetic, Tumor Cells, Cultured, Uterus, Bone Density, Osteocalcin, Apoptosis, Compressive Strength, Mice
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