Abstract
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/Ca(2+) 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.