Biological activity of FGF-23 fragments.
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 1alpha,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.
Berndt
Theresa J
TJ
Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA.
Craig
Theodore A
TA
McCormick
Daniel J
DJ
Lanske
Beate
B
Sitara
Despina
D
Razzaque
Mohammed S
MS
Pragnell
Marlon
M
Bowe
Ann E
AE
O'Brien
Stephen P
SP
Schiavi
Susan C
SC
Kumar
Rajiv
R
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009893:Opossums; D010446:Peptide Fragments / Q000502:physiology*; D010710:Phosphates / Q000652:urine; D011188:Potassium / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010446:Peptide Fragments; D010710:Phosphates; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; D011188:Potassium