Biological activity of FGF-23 fragments

Theresa J. Berndt, Theodore A. Craig, Daniel J. McCormick, Beate Lanske, Despina Sitara, Mohammed S. Razzaque, Marlon Pragnell, Ann E. Bowe, Stephen P. O'Brien, Susan C. Schiavi, Rajiv Kumar

Research output: Contribution to journalArticlepeer-review

Abstract

The phosphaturic activity of intact, full-length, fibroblast growth factor-23 (FGF-23) is well documented. FGF-23 circulates as the intact protein and as fragments generated as the result of proteolysis of the full-length protein. To assess whether short fragments of FGF-23 are phosphaturic, we compared the effect of acute, equimolar infusions of full-length FGF-23 and various FGF-23 fragments carboxyl-terminal to amino acid 176. In rats, intravenous infusions of full-length FGF-23 and FGF-23 176-251 significantly and equivalently increased fractional phosphate excretion (FE Pi) from 14±3 to 32±5% and 15±2 to 33±2% (p<0.001), respectively. Chronic administration of FGF-23 176-251 reduced serum Pi and serum concentrations of 1α,25-dihydroxyvitamin D. Shorter forms of FGF-23 (FGF-23 180-251 and FGF-23 184-251) retained phosphaturic activity. Further shortening of the FGF-23 carboxyl-terminal domain, however, abolished phosphaturic activity, as infusion of FGF-23 206-251 did not increase urinary phosphate excretion. Infusion of a short fragment of the FGF-23 molecule, FGF-23 180-205, significantly increased FE Pi in rats and reduced serum Pi in hyperphosphatemic Fgf-23 -/- knockout mice. The activity of FGF-23 180-251 was confirmed in opossum kidney cells in which the peptide reduced Na+-dependent Pi uptake and enhanced internalization of the Na +-Pi IIa co-transporter. We conclude that carboxyl terminal fragments of FGF-23 are phosphaturic and that a short, 26-amino acid fragment of FGF-23 retains significant phosphaturic activity.

Original languageEnglish (US)
Pages (from-to)615-623
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume454
Issue number4
DOIs
StatePublished - Jul 2007

Keywords

  • 1α,25(OH)D
  • FGF-23
  • Kidney
  • Phosphate
  • Rat

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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