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

• DOI: 10.1172/jci18563
• Publication Date: 2008-02-29T22:00:19Z
• Authors: Theresa Berndt; Theodore A. Craig; Ann E. Bowe; John Vassiliadis; David Reczek; Richard Finnegan; Suzanne M. Jan De...; Susan C. Schiavi; Rajiv Kumar
• Keywords: Hypophosphatemia; Osteomalacia

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 circulating phosphaturic factor antagonizes renal Wnt-signaling. In cultured opossum epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of normal rats over 2 hours increased fractional excretion inorganic (FEPi) from 14% ± 2% to 34% 5% (mean SEM, P < 0.01). Urinary cAMP calcium were unchanged. thyro-parathyroidectomized rats, FEPi 0.7% 0.2% 3.8% 1.2% (P 0.05), demonstrating inhibits reabsorption PTH-independent mechanisms. Administration intact 8 FEPi, decreased serum (1.95 0.1 1.53 0.09 mmol/l, 0.05) but did not alter 1α, 25-dihydroxyvitamin D, 25-hydroxyvitamin D 1α-hydroxylase cytochrome P450, sodium-phosphate cotransporter mRNA concentrations. Infusion Wnt action as demonstrated reduced β-catenin phosphorylated The detectable human patient tumor-induced osteomalacia. Thus, displays phosphatonin-like properties, because it promotes blunts compensatory increases D.