Th17 cells and Tregs determine the catabolic and anabolic effects of PTH in bone

Emory University, Atlanta GA

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Abstract

? DESCRIPTION (provided by applicant): Continuous PTH (cPTH) treatment exerts a bone catabolic activity while intermittent PTH (iPTH) treatment induces bone anabolism. Our published data indicate that the differential effects of cPTH and iPTH is explained by the specific capacity of cPTH and iPTH to induce T cell production of the osteoclastogenic factor TNF? and the pro-osteogenic Wnt ligand Wnt10b, respectively. Preliminary studies in humans and mice show that cPTH and primary hyperparathyroidism expand Th17 cells and increase the production of IL-17A via a TNF dependent mechanism. By contrast, iPTH in mice and Teriparatide (a form of iPTH treatment) in humans expand regulatory T cells (Tregs), an immunosuppressive population of CD4+ T cells. Demonstrating a role for IL-17 and Tregs, we found that in vivo neutralization of IL-17A blocks the increase in RANKL production by osteocytes (OCYs) and osteoblasts (OBs) and prevents the bone loss induced by cPTH. By contrast, Tregs depletion blunts the bone anabolic activity of iPTH. We thus hypothesize that cPTH and iPTH polarize the differentiation of naïve CD4+ T cells into Th17 and Tregs, respectively, and that the differential effects of cPTH and iPTH in bone are explained by the specific capacity of cPTH and iPTH to expand Th17 cells and Tregs. Consequently, in Aim 1 we will: a) determine if cPTH induces Th17 cell expansion by increasing TNFR1 and G?S signaling in CD4+ cells, b) determine the contribution of Th17 cell produced IL-17A to cPTH induced bone loss via conditional deletion of Th17 cells, c) investigate if IL-17A signaling in OCYs and/or OBs is required for cPTH to upregulate RANKL production and induce bone loss. In Aim 2 we will determine: a) if iPTH increases the differentiation of Tregs by signaling directly in CD4+ cells vi PTHR1, b) if PTH increases the differentiation of Tregs by increasing the sensitivity of naïve CD4+ cells to TGF? via a notch dependent mechanism, c) if Tregs deletion blocks the anabolic activity of iPTH, and d) if Tregs potentiate iPTH induced Wnt10 production and bone anabolism by blocking CD28 signaling.