RGD Reference Report - Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. - Rat Genome Database

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

Authors: Berndt, T  Craig, TA  Bowe, AE  Vassiliadis, J  Reczek, D  Finnegan, R  Jan De Beur, SM  Schiavi, SC  Kumar, R 
Citation: Berndt T, etal., J Clin Invest. 2003 Sep;112(5):785-94.
RGD ID: 8554482
Pubmed: PMID:12952927   (View Abstract at PubMed)
PMCID: PMC182208   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI18563   (Journal Full-text)

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 thyro-parathyroidectomized 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 1alpha, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1alpha-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal beta-catenin and increased phosphorylated beta-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 that promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1alpha, 25-dihydroxyvitamin D.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Sfrp4Ratnegative regulation of canonical Wnt signaling pathway involved_inIDA PMID:12952927BHF-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Sfrp4  (secreted frizzled-related protein 4)


Additional Information