title: Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.
abstract: Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.
authors.affiliation: Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Meir
authors.affiliation: Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Karina
authors.initials: K
authors.lastname: Durlacher
authors.affiliation: Amgen, Thousand Oaks, California, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Pathology, Hadassah Hospital, Jerusalem, Israel.
authors.forename: Gail
authors.initials: G
authors.lastname: Amir
authors.affiliation: Amgen, Thousand Oaks, California, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Justin
authors.initials: J
authors.lastname: Silver
authors.affiliation: Department of Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Naveh-Many
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D057966:Calcimimetic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D008297:Male; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics* / Q000378:metabolism*; D010006:Osteoblasts; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology*; D010627:Phenethylamines; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011437:Propylamines; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012886:Skull / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000814:Aniline Compounds; D057966:Calcimimetic Agents; C505605:Fgf23 protein, rat; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger; D005576:Colforsin; D005346:Fibroblast Growth Factors; D017868:Cyclic AMP-Dependent Protein Kinases