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

• Type of Material: Article
• Authors: Jau-Yi Li, Emory University; Patrizia D'Amelio, University of Turin; Jerid Robinson, Emory University; Lindsey D. Walker, Emory University; Chiara Vaccaro, Emory University; Tao Luo, Emory University; Abdul Malik Tyagi, Emory University; Mingcan Yu, Emory University; Michael Reott, Emory University; Francesca Sassi, University of Turin; Ilaria Buondonno, University of Turin; Jonathan Adams, Emory University; M. Neale Weitzmann, Emory University; Giovanni Carlo Isaia, University of Turin; Roberto Pacifici, Emory University
• Language: English
• Date: 2015-11-03
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cmet.2015.09.012
• Title of Journal or Parent Work: Cell Metabolism
• ISSN: 1550-4131
• Volume: 22
• Issue: 5
• Start Page: 799
• End Page: 810
• Grant/Funding Information: JYL was supported by a grant from the National Institutes of Health (AR061453).; This study was supported by grants from the National Institutes of Health (AR54625, DK007298 and RR028009).; MNW was supported in part, by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105) and by NIH grants R01AR059364 and R01AG040013.
• Keywords: bone; Life Sciences & Biomedicine; T cells; TH17 cells; IL-17; Hyperparathyroidism; Endocrinology & Metabolism; Cell Biology; IL-17 antibody; Science & Technology; IL-17R; PTH

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/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.