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

J Clin Invest. 2003 Sep;112(5):785-94. doi: 10.1172/JCI18563.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics
  • Animals
  • Calcitriol / blood
  • Cytochrome P-450 Enzyme System / genetics
  • Fibroblast Growth Factors / physiology
  • Humans
  • Kidney / metabolism*
  • Opossums
  • Osteomalacia / metabolism*
  • Paraneoplastic Syndromes / metabolism*
  • Phosphates / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • Sodium / metabolism
  • Sodium-Phosphate Cotransporter Proteins
  • Steroid Hydroxylases / genetics
  • Symporters / physiology
  • Vitamin D / metabolism
  • Vitamin D3 24-Hydroxylase
  • Wnt Proteins
  • Zebrafish Proteins*

Substances

  • Phosphates
  • Proto-Oncogene Proteins
  • SFRP4 protein, human
  • Sfrp4 protein, rat
  • Sodium-Phosphate Cotransporter Proteins
  • Symporters
  • Wnt Proteins
  • Zebrafish Proteins
  • Vitamin D
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Cytochrome P-450 Enzyme System
  • Sodium
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol