title: Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis.
abstract: Parathyroid-hormone-type 1 receptor (PTH1R) is extensively expressed in key regulatory organs for systemic mineral ion homeostasis, including kidney and bone. We investigated the bone-specific functions of PTH1R in modulating mineral ion homeostasis by generating a novel mouse model in which PTH1R is ablated in the limb mesenchyme using Prx1Cre transgenic mice. Such ablation decreased FGF23 protein and serum levels by 50%, despite normal Fgf23 mRNA levels in long bones. Circulating calcium and PTH levels were unchanged, but inorganic phosphate and 1,25(OH)2D3 levels were significantly decreased and accompanied by elevated urinary calcium and phosphate wasting. Key renal genes for balancing mineral ion homeostasis, calbindinD28k, Klotho, and Napi2a were suppressed by 30-40%. Intermittent hPTH(1-34) injections increased Fgf23 mRNA (7.3-fold), Nurr1 mRNA (3.1-fold), and serum intact-FGF23 (1.6-fold) in controls, but failed to induce Fgf23, Nurr1 mRNA, or intact FGF23 production in mutants. Moreover, a significant elevation in serum C-terminal-FGF23 levels (4-fold) was detected in both genotypes. PTH markedly downregulated Galnt3 expression (2.7-fold) in controls but not in mutants. These results demonstrate the pivotal role of PTH1R in long bones to regulate systemic mineral ion homeostasis and the direct induction of FGF23 by PTH1R signaling.
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Ruiye
authors.initials: R
authors.lastname: Bi
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Densmore
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.affiliation: *Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria beate_lanske@hsdm.harvard.edu.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D064026:Calbindins / Q000235:genetics / Q000378:metabolism; D002113:Calcification, Physiologic; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D010710:Phosphates / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D064026:Calbindins; D002118:Calcium; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D017350:N-Acetylgalactosaminyltransferases; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010710:Phosphates; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717428:Fgf23 protein, mouse; C539883:Nr4a2 protein, mouse
keywords: Galnt3; calcium/phosphate metabolism; kidney-bone mineral diseases