ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2015
A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 33 citations in OpenAlex.
- Targeting the gut-bone axis in osteoporosis: probiotic interventions and other microbiota-based therapeutic strategies.Gut microbes · 2026Review
- Opposing Dynamics of CD4 + Regulatory and CD8 + Foxp3+ T Cells Characterize Immune Imbalance in Rheumatoid Arthritis.Inflammation · 2026Article
- Targeting Periodontitis with Treg-Derived Extracellular Vesicles: Modulation of Macrophages and CD8International journal of molecular sciences · 2026Article
- Identification of common genetic features and pathways for osteoporosis with frozen shoulder by integrated bioinformatics analysis and machine learning.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2026Article
- The role and mechanisms of bone microenvironment regulators in osteoporosis: novel intervention strategies for addressing the challenges of aging.Frontiers in endocrinology · 2026Review
- CD8a + GZMK + T Cells Inhibit Osteoclastogenesis in Postmenopausal Osteoporosis via the p38-MAPK Pathway.Calcified tissue international · 2025Article
- Functional roles of immune cells in osteoporosis.Frontiers in immunology · 2025Review
- Smoking and osteoimmunology: Understanding the interplay between bone metabolism and immune homeostasis.Journal of orthopaedic translation · 2024Review
- Cyclic Adenosine Monophosphate (cAMP)-Dependent Phosphodiesterase Inhibition Promotes Bone Anabolism Through CD8JBMR plus · 2022Article
- Melatonin inhibits RANKL‑induced osteoclastogenesis through the miR‑882/Rev‑erbα axis in Raw264.7 cells.International journal of molecular medicine · 2021Article
- T-Cell Mediated Inflammation in Postmenopausal Osteoporosis.Frontiers in immunology · 2021Review
- CD39 Produced from Human GMSCs Regulates the Balance of Osteoclasts and Osteoblasts through the Wnt/β-Catenin Pathway in Osteoporosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss.Theranostics · 2020Article
- Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice.Rheumatology (Oxford, England) · 2018Article
- Reduced bone loss in a murine model of postmenopausal osteoporosis lacking complement component 3.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2018Article
- The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status.International journal of environmental research and public health · 2017Article
- Inflammatory osteolysis: a conspiracy against bone.The Journal of clinical investigation · 2017Review
- Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate.Frontiers in bioengineering and biotechnology · 2017Review
- Physiological and pathophysiological bone turnover - role of the immune system.Nature reviews. Endocrinology · 2016Review
- Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
TNF-α and IL-17 secreted by proinflammatory T cells (T(EFF)) promote bone erosion by activating osteoclasts. We previously demonstrated that in addition to bone resorption, osteoclasts act as antigen-presenting cells to induce FoxP3 in CD8 T cells (Tc(REG)). The osteoclast-induced regulatory CD8 T cells limit bone resorption in ovariectomized mice (a murine model of postmenopausal osteoporosis). Here we show that although low-dose receptor activator of NF-κB ligand (RANKL) maximally induces Tc(REG) via Notch signaling pathway to limit bone resorption, high-dose RANKL promotes bone resorption. In vitro, both TNF-α and IL-17, cytokines that are abundant in ovariectomized animals, suppress Tc(REG) induction by osteoclasts by repressing Notch ligand expression in osteoclasts, but this effect can be counteracted by addition of RANKL. Ovariectomized mice treated with low-dose RANKL induced Tc(REG) that suppressed bone resorption, decreased T(EFF) levels, and increased bone formation. High-dose RANKL had the expected osteolytic effect. Low-dose RANKL administration in ovariectomized mice lacking CD8 T cells was also osteolytic, confirming that Tc(REG) mediate this bone anabolic effect. Our results show that although RANKL directly stimulates osteoclasts to resorb bone, it also controls the osteoclasts' ability to induce regulatory T cells, engaging an important negative feedback loop. In addition to the conceivable clinical relevance to treatment of osteoporosis, these observations have potential relevance to induction of tolerance and autoimmune diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.