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This Article Full Text Full Text (PDF) All Versions of this Article: 290/2/F450    most recent 00234.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Syal, A. Articles by Baum, M. Search for Related Content PubMed PubMed Citation Articles by Syal, A. Articles by Baum, M.

Fibroblast growth factor-23 increases mouse PGE₂ production in vivo and in vitro

Departments of ¹Pediatrics and ²Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and ³Applied Genomics, Genzyme Corporation, Framingham, Massachusetts

Submitted 6 June 2005 ; accepted in final form 31 August 2005

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE₂ levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE₂ production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE₂ production, an effect that was inhibited by 50 µM PD-98059 and 10 µM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a 10-fold increase in PGE₂ excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE₂ inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE₂. In conclusion, FGF-23 increases urinary and renal tubular PGE₂ production via the MAP kinase pathway and PGE₂ inhibits proximal tubule phosphate transport.

volume absorption; in vitro microperfusion; NaPi-2a; rickets; prostaglandin E₂