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

Details

Serval ID
serval:BIB_48D61DA37E7E
Type
Article: article from journal or magazin.
Collection
Publications
Title
IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.
Journal
Cell metabolism
Author(s)
Li J.Y., D'Amelio P., Robinson J., Walker L.D., Vaccaro C., Luo T., Tyagi A.M., Yu M., Reott M., Sassi F., Buondonno I., Adams J., Weitzmann M.N., Isaia G.C., Pacifici R.
ISSN
1932-7420 (Electronic)
ISSN-L
1550-4131
Publication state
Published
Issued date
03/11/2015
Peer-reviewed
Oui
Volume
22
Number
5
Pages
799-810
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Animals, Bone Diseases, Metabolic/drug therapy, Bone Diseases, Metabolic/etiology, Bone Diseases, Metabolic/metabolism, Bone Diseases, Metabolic/pathology, Calcium Channel Blockers/therapeutic use, Humans, Hyperparathyroidism, Primary/complications, Hyperparathyroidism, Primary/drug therapy, Hyperparathyroidism, Primary/metabolism, Hyperparathyroidism, Primary/pathology, Interleukin-17/biosynthesis, Interleukin-17/metabolism, Mice, Receptors, Tumor Necrosis Factor, Type I/biosynthesis, Signal Transduction, T-Lymphocytes/metabolism, T-Lymphocytes/pathology, Tumor Necrosis Factor-alpha/biosynthesis, IL-17, IL-17 antibody, IL-17R, PTH, T cells, Th17 cells, bone, hyperparathyroidism
Pubmed
Web of science
Open Access
Yes
Create date
13/01/2020 16:00
Last modification date
14/01/2020 6:26
Usage data