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Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α
Open accessAbstract
Physiologic osteoclast renewal results from the differentiation of bone marrow monocytes (BMMs) into osteoclasts, a process induced by the simultaneous stimulation of osteoclast precursors by macrophage colonystimulating factor (M-CSF) and a TNF-related factor known as receptor activator of NF-κB ligand (RANKL; also known as OPGL, TRANCE, or ODF) (1-3).Although upregulation of osteoclast formation is recognized as the main mechanism by which estrogen deficiency induces bone loss (4, 5), the responsible cells and cytokines are not completely understood.Bone marrow stromal cells are essential for physiologic osteoclast renewal because they represent a major source of RANKL and M-CSF and provide a physical support for nascent osteoclasts (6).However, in stimulated conditions additional bone marrow cells contribute to regulate osteoclast formation by producing soluble and membrane-bound pro-and antiosteoclastogenic cytokines.Among them are activated T cells, which stimulate osteoclast formation through increased production of RANKL, a phenomenon that contributes to inflammation-induced bone loss (7).T cells express estrogen receptors, and estrogen directly regulates T-cell function and cytokine production (8-11).Moreover, T-cell subset alterations occur in women with postmenopausal osteoporosis (12, 13).Taken together, these findings suggest that T cells may contribute to enhanced osteoclast formation and induce bone loss not only during inflammation, but also in conditions of estrogen deficiency.In this study we have investigated the role of T cells in ovariectomy-induced bone loss.We report that ovariectomy-enhanced T-cell production of TNF-α, which, acting through the TNF-α receptor p55, augments M-CSF-and RANKL-induced osteoclastogenesis.We also show that ovariectomy failed to induce bone loss, stimulate bone resorption, and increase osteoclast formation in T-cell deficient mice, establishing T cells as essential mediators of the bone-wasting effects of estrogen deficiency in vivo. Methods Experimental protocol.All animal procedures were approved by the Animal Care and Use Committee of Barnes-Jewish Hospital.Wild-type C57BL/6 mice, C57BL/6 homozygous (nu/nu) athymic nude mice (14), and heterozygous (nu/+) euthymic control littermates were obtained from Taconic Farms Inc. (Germantown, New York, USA).C57BL/6 mice lacking either TNF-α receptor 1 (p55 -/-) or TNF-α receptor II (p75 -/-) and wild-type controls of the same genetic background were obtained from Jackson Laboratories (Bar Harbor, Maine, USA).At 5 weeks of age mice were either sham operated or ovariectomized (OVX), and either left untreated or treated with 17β estradiol (0.16 µg/d) for 4 weeks as described (15,16).In vitro osteoclast generation, cytokine neutralization, and TNF-α assay.Bone marrow cells were either cultured unfractionated or depleted of stromal cells by adherence for 12 hours.The nonadherent fraction was used as a source of T cells and BMM precursors and was found to
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“In addition, estrogen inhibits osteoclast formation by reducing the levels of other osteoclastogenic cytokines such as IL-1, IL-6, IL-11, TNF-α, TNF-β, and M-CSF [160, 161].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [161]
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“We proposed that T cell-produced TNF is required for ovxinduced bone loss based on the findings that no bone loss occurred and no increased TNF production was detected in T cell-null mice or mice depleted of T cells (40,53).”
From Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics (2016) · cites this paper as [40]
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Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
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OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
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The TNF and TNF Receptor Superfamilies
Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00237-9 · Cited by 3,650
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
The complex role of estrogens in inflammation
Straub, R. H. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0001 · Cited by 1,950
Genetic regulation of osteoclast development and function
Teitelbaum, S. L., & Ross, F. P. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1122 · Cited by 1,720
Feng, X., & McDonald, J. M. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130203 · Cited by 1,272
Metadata
- Authors
- Cenci, S., Weitzmann, M. N., Roggia, C., Namba, N., Novack, D., Woodring, J., & Pacifici, R.
- Affiliations
- Barnes-Jewish Hospital (US)
- Corresponding author
- Pacifici, Roberto
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2000-11-15
- Volume
- 106
- Issue
- 10
- Pages
- 1229-1237
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC381439
- OpenAlex
- W2133281510
- Cited by
- 705
- References
- 57
- Citations by year
- 2026: 30 · 2025: 30 · 2024: 14 · 2023: 25 · 2022: 23 · 2021: 27 · 2020: 35 · 2019: 25 · 2018: 19 · 2017: 34 · 2016: 33 · 2015: 37 · 2014: 32 · 2013: 32 · 2012: 28
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arthritis Foundation
- Eli Lilly and Company
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041412, AR41412, AR-13534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- estrogen deficiency, bone loss, ovariectomy, T cells, TNF-α, osteoclastogenesis, RANKL, macrophage colony-stimulating factor, TNF receptor p55, postmenopausal osteoporosis, bone resorption, nude mice, estrogen receptor, mesenchymal stem cells, T cell deficiency
- MeSH terms
- Animals, Bone Resorption, Carrier Proteins, Cells, Cultured, Estrogens, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Nude, Osteoclasts, Ovariectomy, T-Lymphocytes, Tumor Necrosis Factor-alpha, Antigens, CD, Macrophage Colony-Stimulating Factor, Receptors, Tumor Necrosis Factor, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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