title: FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.
abstract: The functional interaction between fibroblast growth factor 23 (FGF-23) and Klotho in the control of vitamin D and phosphate homeostasis is manifested by the largely overlapping phenotypes of Fgf23- and Klotho-deficient mouse models. However, to date, targeted inactivation of FGF receptors (FGFRs) has not provided clear evidence for an analogous function of FGFRs in this process. Here, by means of pharmacologic inhibition of FGFRs, we demonstrate their involvement in renal FGF-23/Klotho signaling and elicit their role in the control of phosphate and vitamin D homeostasis. Specifically, FGFR loss of function counteracts renal FGF-23/Klotho signaling, leading to deregulation of Cyp27b1 and Cyp24a1 and the induction of hypervitaminosis D and hyperphosphatemia. In turn, this initiates a feedback response leading to high serum levels of FGF-23. Further, we show that FGFR inhibition blocks Fgf23 transcription in bone and that this is dominant over vitamin D-induced Fgf23 expression, ultimately impinging on systemic FGF-23 protein levels. Additionally, we identify Fgf23 as a specific target gene of FGF signaling in vitro. Thus, in line with Fgf23- and Klotho-deficient mouse models, our study illustrates the essential function of FGFRs in the regulation of vitamin D and phosphate levels. Further, we reveal FGFR signaling as a novel in vivo control mechanism for Fgf23 expression in bone, suggesting a dual function of FGFRs in the FGF-23/Klotho pathway leading to vitamin D and phosphate homeostasis.
authors.affiliation: Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Wöhrle
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.forename: Noemie
authors.initials: N
authors.lastname: Beluch
authors.forename: Swann
authors.initials: S
authors.lastname: Gaulis
authors.forename: Christelle
authors.initials: C
authors.lastname: Stamm
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheibler
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Anne
authors.initials: A
authors.lastname: Thuery
authors.forename: Joseph
authors.initials: J
authors.lastname: Brueggen
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Hynes
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Diana
authors.initials: D
authors.lastname: Graus-Porta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D060888:Real-Time Polymerase Chain Reaction; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014807:Vitamin D / Q000502:physiology*
chemical_list: C000717428:Fgf23 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23