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Author Notes:

Address correspondence to: Roberto Pacifici, M.D., Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, 101 Woodruff Circle, Room 1309, Atlanta, GA 30322, Telephone: 404-712-8420, Fax: 404-727-1300, roberto.pacifici@emory.edu.

PDA, FS, IB and GCI designed the human studies, performed the human research, and analyzed the human data.

RP, JYL and MNW designed the animal study/protocols.

YL, JR, LDW, CV, TL, AMT, MY, MR, and JA performed the animal research and analyzed the data.

RP wrote the manuscript and was the principle investigator.

We are grateful to Prof. L. Richiardi (University of Turin, Italy) for his assistance with the statistical analysis of the human data, Dr. Weinstein (NIH) for providing the Gas fl/fl mice and to Amgen, Inc for providing the IL-17RA−/− mice.

Disclosures: The authors state that they have no conflicts of interest.


Research Funding:

This study was supported by grants from the National Institutes of Health (AR54625, DK007298 and RR028009).

JYL was supported by a grant from the National Institutes of Health (AR061453).

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.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Endocrinology & Metabolism
  • PTH
  • Hyperparathyroidism
  • T cells
  • TH17 cells
  • IL-17
  • IL-17R
  • IL-17 antibody
  • bone

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

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Journal Title:

Cell Metabolism


Volume 22, Number 5


, Pages 799-810

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2015 Elsevier Inc.

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