title: Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production.
abstract: Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1β (IL-1β) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1β injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1β injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3(ko) mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: valentin.david@northwestern.edu.
authors.forename: Valentin
authors.initials: V
authors.lastname: David
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: Martin
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Isakova
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Spaulding
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ramirez
authors.affiliation: Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen-Bullough
authors.affiliation: Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chia Chi
authors.initials: CC
authors.lastname: Sun
authors.affiliation: Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Nephrology Division, Program in Membrane Biology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D005269:Femur / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000097:blood*; D053583:Interleukin-1beta / Q000494:pharmacology; D007501:Iron / Q000097:blood*; D000090463:Iron Deficiencies; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C000717428:Fgf23 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017262:Siderophores; C057112:type IV collagen alpha3 chain; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D007501:Iron; D003676:Deferoxamine
keywords: FGF23; anemia; bone; hypoxia; inflammation; mineral metabolism