Endothelin receptor B controls the production of fibroblast growth factor 23

Endothelin-1 (ET-1) is a member of the endothelin family of peptide hormones first discovered as endothelium-derived mediators regulating vascular tone. ET-1 also regulates the proliferation and differentiation of bone cells that synthesize fibroblast growth factor 23 (FGF23). FGF23 is a hormone controlling renal phosphate and vitamin D metabolism. Here, we studied the role of ET-1 and endothelin receptor B (ETB) for FGF23 production. Fgf23 gene expression was studied in IDG-SW3 bone cells by quantitative RT-PCR. ETB-expressing (etb^+/+ ) and rescued ETB-deficient mice (etb^-/- ) were studied in metabolic cages. Their serum FGF23, PTH, and 1,25(OH)₂ D₃ concentrations were determined by ELISA, serum and urinary phosphate and Ca²⁺ by photometric methods. ET-1 and ETB agonist sarafotoxin 6c suppressed Fgf23 mRNA in IDG-SW3 cells. Serum C-terminal and intact FGF23 as well as bone Fgf23 mRNA levels were significantly higher in etb^-/- mice than in etb^+/+ mice. Renal phosphate excretion was significantly higher in etb^-/- mice despite lower phosphate levels. In addition, etb^-/- animals exhibited calciuria and a significantly higher serum 1,25(OH)₂ D₃ concentration compared to etb^+/+ mice. In conclusion, ETB-dependent ET-1 signaling is a potent suppressor of FGF23 formation. This effect is likely to be of clinical relevance given the use of endothelin receptor antagonists in various diseases.