Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent

Theresa Berndt, Theodore A. Craig, Ann E. Bowe, John Vassiliadis, David Reczek, Richard Finnegan, Suzanne M. Jan De Beur, Susan C. Schiavi, Rajiv Kumar

Research output: Contribution to journalArticle

Abstract

Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14% ± 2% to 34% ± 5% (mean ± SEM, P < 0.01). Urinary cAMP and calcium excretion were unchanged. In thyroparathyroidectomized rats, sFRP-4 increased FEPi from 0.7% ± 0.2% to 3.8% ± 1.2% (P < 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 ± 0.1 to 1.53 ± 0.09 mmol/l, P < 0.05) but did not alter serum 1α, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1α-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal β-catenin and increased phosphorylated β-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein thar promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1α, 25-dihydroxyvitamin D.

Original languageEnglish (US)
Pages (from-to)785-794
Number of pages10
JournalJournal of Clinical Investigation
Volume112
Issue number5
DOIs
StatePublished - Sep 2003

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Neoplasms
Kidney
Familial Hypophosphatemia
Hypophosphatemia
Catenins
Phosphates
Serum
Sodium-Phosphate Cotransporter Proteins
rat Sfrp4 protein
Opossums
Osteomalacia
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Proteins
Epithelial Cells
Calcium
Messenger RNA
1,25-dihydroxyvitamin D

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Berndt, T., Craig, T. A., Bowe, A. E., Vassiliadis, J., Reczek, D., Finnegan, R., ... Kumar, R. (2003). Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. Journal of Clinical Investigation, 112(5), 785-794. https://doi.org/10.1172/JCI200318563

Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. / Berndt, Theresa; Craig, Theodore A.; Bowe, Ann E.; Vassiliadis, John; Reczek, David; Finnegan, Richard; Jan De Beur, Suzanne M.; Schiavi, Susan C.; Kumar, Rajiv.

In: Journal of Clinical Investigation, Vol. 112, No. 5, 09.2003, p. 785-794.

Research output: Contribution to journalArticle

Berndt, T, Craig, TA, Bowe, AE, Vassiliadis, J, Reczek, D, Finnegan, R, Jan De Beur, SM, Schiavi, SC & Kumar, R 2003, 'Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent', Journal of Clinical Investigation, vol. 112, no. 5, pp. 785-794. https://doi.org/10.1172/JCI200318563
Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. Journal of Clinical Investigation. 2003 Sep;112(5):785-794. https://doi.org/10.1172/JCI200318563
Berndt, Theresa ; Craig, Theodore A. ; Bowe, Ann E. ; Vassiliadis, John ; Reczek, David ; Finnegan, Richard ; Jan De Beur, Suzanne M. ; Schiavi, Susan C. ; Kumar, Rajiv. / Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. In: Journal of Clinical Investigation. 2003 ; Vol. 112, No. 5. pp. 785-794.
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abstract = "Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14{\%} ± 2{\%} to 34{\%} ± 5{\%} (mean ± SEM, P < 0.01). Urinary cAMP and calcium excretion were unchanged. In thyroparathyroidectomized rats, sFRP-4 increased FEPi from 0.7{\%} ± 0.2{\%} to 3.8{\%} ± 1.2{\%} (P < 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 ± 0.1 to 1.53 ± 0.09 mmol/l, P < 0.05) but did not alter serum 1α, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1α-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal β-catenin and increased phosphorylated β-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein thar promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1α, 25-dihydroxyvitamin D.",
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