FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.
Oncogenic osteomalacia (OOM), X-linked hypophosphatemia (XLH), and autosomal dominant hypophosphatemic rickets (ADHR) are phenotypically similar disorders characterized by hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum calcitriol concentrations, normal serum concentrations of calcium and parathyroid hormone, and defective skeletal mineralization. XLH results from mutations in the PHEX gene, encoding a membrane-bound endopeptidase, whereas ADHR is associated with mutations of the gene encoding FGF-23. Recent evidence that FGF-23 is expressed in mesenchymal tumors associated with OOM suggests that FGF-23 is responsible for the phosphaturic activity previously termed "phosphatonin." Here we show that both wild-type FGF-23 and the ADHR mutant, FGF-23(R179Q), inhibit phosphate uptake in renal epithelial cells. We further show that the endopeptidase, PHEX, degrades native FGF-23 but not the mutant form. Our results suggest that FGF-23 is involved in the pathogenesis of these three hypophosphatemic disorders and directly link PHEX and FGF-23 within the same biochemical pathway.
Bowe
A E
AE
Applied Genomics, Genzyme, Framingham, Massachusetts 01701-9322, USA.
Finnegan
R
R
Jan de Beur
S M
SM
Cho
J
J
Levine
M A
MA
Kumar
R
R
Schiavi
S C
SC
D019943:Amino Acid Substitution; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008637:Mesenchymoma / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016366:Open Reading Frames; D009893:Opossums; D010018:Osteomalacia / Q000235:genetics*; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010710:Phosphates / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
C000717427:FGF23 protein, human; D010710:Phosphates; D011506:Proteins; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D010450:Endopeptidases; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human