Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice
Open accessAbstract
The loss of estrogen (E2) initiates a rapid phase of bone loss leading to osteoporosis in one-half of postmenopausal women, but the mechanism is not fully understood. Here, we show for the first time how loss of E2 activates low-grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E2 regulates the abundance of dendritic cells (DCs) that express IL-7 and IL-15 by inducing the Fas ligand (FasL) and apoptosis of the DC. In the absence of E2, DCs become long-lived, leading to increased IL-7 and IL-15. We find that IL-7 and IL-15 together, but not alone, induced antigen-independent production of IL-17A and TNFα in a subset of memory T cells (TMEM). OVX of mice with T-cell–specific ablation of IL15RA showed no IL-17A and TNFα expression, and no increase in bone resorption or bone loss, confirming the role of IL-15 in activating the TMEM and the need for inflammation. Our results provide a new mechanism by which E2 regulates the immune system, and how menopause leads to osteoporosis. The low-grade inflammation is likely to cause or contribute to other comorbidities observed postmenopause. © 2020 American Society for Bone and Mineral Research.
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Loss of estrogen promotes low-grade T-cell-regulated inflammation.
“Cline-Smith et al. (2020) further strengthened this model by demonstrating a relationship between the loss of estrogen and the promotion of low-grade T-cell-regulated inflammation [21].”
From Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics (2023) · cites this paper as [21]
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Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics
Adejuyigbe, B., Kallini, J., Chiou, D., & Kallini, J. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914583 · Cited by 148 · see citing works
- Authors
- Cline-Smith, A., Axelbaum, A., Shashkova, E., Chakraborty, M., Sanford, J., Panesar, P., Peterson, M., Cox, L., Baldan, A., Veis, D., & Aurora, R.
- Affiliations
- Saint Louis University (US)
- Washington University in St. Louis (US)
- Department of Biochemistry and Molecular Biology Saint Louis University School of Medicine St. Louis MO USA
- Division of Bone and Mineral Diseases Washington University School of Medicine in St. Louis St. Louis MO USA
- Corresponding author
- Aurora, Rajeev
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-01-29
- Volume
- 35
- Issue
- 6
- Pages
- 1174-1187
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- PMC
- PMC8061311
- OpenAlex
- W3003921069
- Cited by
- 108
- References
- 131
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 20 · 2023: 17 · 2022: 15 · 2021: 9 · 2020: 4
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Washington University in St. Louis
- Saint Louis University School of Medicine
- 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 › Genetics › Estrogen and related hormone effects
- Keywords
- ovariectomy, estrogen deficiency, postmenopausal osteoporosis, low-grade inflammation, memory T cells, dendritic cells, IL-15, IL-7, IL-17A, TNF-α, Fas ligand, dendritic cell apoptosis, bone resorption, bone loss, menopause
- MeSH terms
- Animals, Female, Humans, Immunologic Memory, Inflammation, Osteoporosis, Ovariectomy, T-Lymphocytes, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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