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FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.
J Bone Miner Res. 2011 Oct; 26(10):2486-97.JB

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+Show Affiliations

Novartis Institutes for BioMedical Research, Disease Area Oncology, Basel, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21812026

Citation

Wöhrle, Simon, et al. "FGF Receptors Control Vitamin D and Phosphate Homeostasis By Mediating Renal FGF-23 Signaling and Regulating FGF-23 Expression in Bone." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 26, no. 10, 2011, pp. 2486-97.
Wöhrle S, Bonny O, Beluch N, et al. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res. 2011;26(10):2486-97.
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. (2011). FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 26(10), 2486-97. https://doi.org/10.1002/jbmr.478
Wöhrle S, et al. FGF Receptors Control Vitamin D and Phosphate Homeostasis By Mediating Renal FGF-23 Signaling and Regulating FGF-23 Expression in Bone. J Bone Miner Res. 2011;26(10):2486-97. PubMed PMID: 21812026.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. AU - Wöhrle,Simon, AU - Bonny,Olivier, AU - Beluch,Noemie, AU - Gaulis,Swann, AU - Stamm,Christelle, AU - Scheibler,Marcel, AU - Müller,Matthias, AU - Kinzel,Bernd, AU - Thuery,Anne, AU - Brueggen,Joseph, AU - Hynes,Nancy E, AU - Sellers,William R, AU - Hofmann,Francesco, AU - Graus-Porta,Diana, PY - 2011/8/4/entrez PY - 2011/8/4/pubmed PY - 2012/1/24/medline SP - 2486 EP - 97 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 26 IS - 10 N2 - 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. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/21812026/FGF_receptors_control_vitamin_D_and_phosphate_homeostasis_by_mediating_renal_FGF_23_signaling_and_regulating_FGF_23_expression_in_bone_ L2 - https://doi.org/10.1002/jbmr.478 DB - PRIME DP - Unbound Medicine ER -