IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice

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 ant...

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Veröffentlicht in:Cell metabolism 2015-11, Vol.22 (5), p.799-810
Hauptverfasser: Li, Jau-Yi, D’Amelio, Patrizia, Robinson, Jerid, Walker, Lindsey D., Vaccaro, Chiara, Luo, Tao, Tyagi, Abdul Malik, Yu, Mingcan, Reott, Michael, Sassi, Francesca, Buondonno, Ilaria, Adams, Jonathan, Weitzmann, M. Neale, Isaia, Giovanni Carlo, Pacifici, Roberto
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Increased production of IL-17A in humans affected by PHPT•Treatment with cPTH expands Th17 cells and IL-17A production in mice•Neutralization of IL-17A or silencing of IL-17RA block cPTH-induced bone loss•cPTH increases the differentiation of Th17 cells via TNF and GαS signaling Li et al. show that primary hyperparathyroidism in humans and PTH treatment in mice induce bone loss by increasing production of the inflammatory cytokine IL-17A. Targeting the IL-17 pathway, including treatment with the prescription calcium channel blocker drug, diltiazem, in mice prevents cPTH-induced bone loss, suggesting new treatment avenues.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2015.09.012