A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells. (21st May 2015)

• Record Type: Journal Article
• Authors: Buchwald, Zachary S; Yang, Chang; Nellore, Suman; Shashkova, Elena V; Davis, Jennifer L; Cline, Anna; Ko, Je; Novack, Deborah V; DiPaolo, Richard; Aurora, Rajeev
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 8(2015:Aug.)
• Page Start: 1508
• Page End: 1522
• Publication Date: 2015-05-21
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2472
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2472-sec-0001" sec-type="section"> <p>TNF‐α and IL‐17 secreted by proinflammatory T cells (T<sub>EFF</sub>) 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<sub>REG</sub>). 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<sub>REG</sub> 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<sub>REG</sub> 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<sub>REG</sub> that suppressed bone resorption, decreased T<sub>EFF</sub> 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<sub>REG</sub> 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. © 2015 American Society for Bone and Mineral Research.</p> </sec> </abstract>