IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.
Détails
ID Serval
serval:BIB_48D61DA37E7E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.
Périodique
Cell metabolism
ISSN
1932-7420 (Electronic)
ISSN-L
1550-4131
Statut éditorial
Publié
Date de publication
03/11/2015
Peer-reviewed
Oui
Volume
22
Numéro
5
Pages
799-810
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
13/01/2020 17:00
Dernière modification de la notice
14/01/2020 7:26