title: IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.
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.
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jau-Yi
authors.initials: JY
authors.lastname: Li
authors.affiliation: Gerontology Section, Department of Medical Sciences, University of Torino, Corso Bramante 88/90, 10126 Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Amelio
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jerid
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Walker
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Vaccaro
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Abdul Malik
authors.initials: AM
authors.lastname: Tyagi
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Mingcan
authors.initials: M
authors.lastname: Yu
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Reott
authors.affiliation: Gerontology Section, Department of Medical Sciences, University of Torino, Corso Bramante 88/90, 10126 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sassi
authors.affiliation: Gerontology Section, Department of Medical Sciences, University of Torino, Corso Bramante 88/90, 10126 Torino, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Buondonno
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adams
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA; Atlanta Department of Veterans Affairs Medical Center, Decatur, GA 30033, USA.
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.affiliation: Gerontology Section, Department of Medical Sciences, University of Torino, Corso Bramante 88/90, 10126 Torino, Italy.
authors.forename: Giovanni Carlo
authors.initials: GC
authors.lastname: Isaia
authors.affiliation: Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA; Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA 30322, USA. Electronic address: roberto.pacifici@emory.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacifici
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D002121:Calcium Channel Blockers; C508717:IL17A protein, human; D020381:Interleukin-17; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha
keywords: IL-17; IL-17 antibody; IL-17R; PTH; T cells; Th17 cells; bone; hyperparathyroidism