title: A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells.
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.
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Zachary S
authors: ZS
authors: Buchwald
authors: Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
authors: Chang
authors: C
authors: Yang
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Suman
authors: S
authors: Nellore
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Elena V
authors: EV
authors: Shashkova
authors: Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
authors: Jennifer L
authors: JL
authors: Davis
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Anna
authors: A
authors: Cline
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Je
authors: J
authors: Ko
authors: Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
authors: Deborah V
authors: DV
authors: Novack
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Richard
authors: R
authors: DiPaolo
authors: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Rajeev
authors: R
authors: Aurora
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010024:Osteoporosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: Bone histomorphometry <ANALYSIS/QUANTITATION OF BONE; Genetic animal models <ANIMAL MODELS; Osteoclasts <CELLS OF BONE; Osteoimmunology <SYSTEMS BIOLOGY-BONE INTERACTORS; Osteoporosis <DISEASES AND DISORDERS OF/RELATED TO BONE
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