[PDF][PDF] IL-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice

JY Li, P D'Amelio, J Robinson, LD Walker, C Vaccaro… - Cell metabolism, 2015 - cell.com
JY Li, P D'Amelio, J Robinson, LD Walker, C Vaccaro, T Luo, AM Tyagi, M Yu, M Reott…
Cell metabolism, 2015cell.com
Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by
continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is
upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by
parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A
receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and
bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF) …
Summary
Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4+ cells. Moreover, cPTH enhances the sensitivity of naive CD4+ cells to TNF via GαS/cAMP/Ca2+ signaling. Accordingly, conditional deletion of GαS in CD4+ cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism.
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