Biological activity of FGF-23 fragments

Theresa J. Berndt, Theodore A. Craig, Daniel J Mc Cormick, 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 journalArticle

37 Citations (Scopus)

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

Fingerprint

Bioactivity
fibroblast growth factor 23
Rats
Serum
Phosphates
Proteolysis
Symporters
Opossums
Amino Acids
Intravenous Infusions
Knockout Mice

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Biological activity of FGF-23 fragments. / Berndt, Theresa J.; Craig, Theodore A.; Mc Cormick, Daniel J; Lanske, Beate; Sitara, Despina; Razzaque, Mohammed S.; Pragnell, Marlon; Bowe, Ann E.; O'Brien, Stephen P.; Schiavi, Susan C.; Kumar, Rajiv.

In: Pflugers Archiv European Journal of Physiology, Vol. 454, No. 4, 07.2007, p. 615-623.

Research output: Contribution to journalArticle

Berndt, TJ, Craig, TA, Mc Cormick, DJ, Lanske, B, Sitara, D, Razzaque, MS, Pragnell, M, Bowe, AE, O'Brien, SP, Schiavi, SC & Kumar, R 2007, 'Biological activity of FGF-23 fragments', Pflugers Archiv European Journal of Physiology, vol. 454, no. 4, pp. 615-623. https://doi.org/10.1007/s00424-007-0231-5
Berndt, Theresa J. ; Craig, Theodore A. ; Mc Cormick, Daniel J ; Lanske, Beate ; Sitara, Despina ; Razzaque, Mohammed S. ; Pragnell, Marlon ; Bowe, Ann E. ; O'Brien, Stephen P. ; Schiavi, Susan C. ; Kumar, Rajiv. / Biological activity of FGF-23 fragments. In: Pflugers Archiv European Journal of Physiology. 2007 ; Vol. 454, No. 4. pp. 615-623.
@article{34a29fc0d8de427da26bec8e2a1eb573,
title = "Biological activity of FGF-23 fragments",
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.",
keywords = "1α,25(OH)D, FGF-23, Kidney, Phosphate, Rat",
author = "Berndt, {Theresa J.} and Craig, {Theodore A.} and {Mc Cormick}, {Daniel J} and Beate Lanske and Despina Sitara and Razzaque, {Mohammed S.} and Marlon Pragnell and Bowe, {Ann E.} and O'Brien, {Stephen P.} and Schiavi, {Susan C.} and Rajiv Kumar",
year = "2007",
month = "7",
doi = "10.1007/s00424-007-0231-5",
language = "English (US)",
volume = "454",
pages = "615--623",
journal = "Pfl{\"u}gers Archiv - European Journal of Physiology",
issn = "0031-6768",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Biological activity of FGF-23 fragments

AU - Berndt, Theresa J.

AU - Craig, Theodore A.

AU - Mc Cormick, Daniel J

AU - Lanske, Beate

AU - Sitara, Despina

AU - Razzaque, Mohammed S.

AU - Pragnell, Marlon

AU - Bowe, Ann E.

AU - O'Brien, Stephen P.

AU - Schiavi, Susan C.

AU - Kumar, Rajiv

PY - 2007/7

Y1 - 2007/7

N2 - 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.

AB - 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.

KW - 1α,25(OH)D

KW - FGF-23

KW - Kidney

KW - Phosphate

KW - Rat

UR - http://www.scopus.com/inward/record.url?scp=34249866191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249866191&partnerID=8YFLogxK

U2 - 10.1007/s00424-007-0231-5

DO - 10.1007/s00424-007-0231-5

M3 - Article

VL - 454

SP - 615

EP - 623

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

SN - 0031-6768

IS - 4

ER -