title: Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.
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.
authors.affiliation: Department of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Berndt
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Craig
authors.forename: Ann E
authors.initials: AE
authors.lastname: Bowe
authors.forename: John
authors.initials: J
authors.lastname: Vassiliadis
authors.forename: David
authors.initials: D
authors.lastname: Reczek
authors.forename: Richard
authors.initials: R
authors.lastname: Finnegan
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Jan De Beur
authors.forename: Susan C
authors.initials: SC
authors.lastname: Schiavi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D002117:Calcitriol / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D009893:Opossums; D010018:Osteomalacia / Q000378:metabolism*; D010257:Paraneoplastic Syndromes / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D012964:Sodium / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins; D013250:Steroid Hydroxylases / Q000235:genetics; D027981:Symporters / Q000502:physiology; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D003577:Cytochrome P-450 Enzyme System; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D010710:Phosphates; D011518:Proto-Oncogene Proteins; D012964:Sodium; D050608:Sodium-Phosphate Cotransporter Proteins; D013250:Steroid Hydroxylases; D027981:Symporters; D014807:Vitamin D; D065668:Vitamin D3 24-Hydroxylase; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C498455:Sfrp4 protein, rat