FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.

Details

Serval ID
serval:BIB_364281994870
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.
Journal
Journal of Bone and Mineral Research
Author(s)
Wöhrle S., Bonny O., Beluch N., Gaulis S., Stamm C., Scheibler M., Müller M., Kinzel B., Thuery A., Brueggen J., Hynes N.E., Sellers W.R., Hofmann F., Graus-Porta D.
ISSN
1523-4681 (Electronic)
ISSN-L
0884-0431
Publication state
Published
Issued date
2011
Volume
26
Number
10
Pages
2486-2497
Language
english
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.
Keywords
Animals, Blotting, Western, Bone and Bones/metabolism, Cell Line, Fibroblast Growth Factors/blood, Fibroblast Growth Factors/metabolism, Gene Expression Regulation, Homeostasis/physiology, Kidney/metabolism, Mice, Mice, Inbred BALB C, Real-Time Polymerase Chain Reaction, Receptors, Fibroblast Growth Factor/physiology, Signal Transduction/physiology, Vitamin D/physiology
Pubmed
Web of science
Create date
21/10/2011 10:35
Last modification date
20/10/2020 14:41
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