Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors.
Oncogenic osteomalacia (OO), a tumor-associated phosphate-wasting syndrome, provides an opportunity to identify regulators of renal phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal phosphate transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent phosphate transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no phosphate transport inhibitory activity. Furthermore, only small amounts of FGF23 were present in inhibitory conditioned medium, comparable to concentrations found in conditioned medium with no phosphate transport inhibitory activity. Thus, FGF7 was specifically identified when selecting for in vitro phosphate transport inhibitory activity of tumor-derived cultures and was confirmed as a potent inhibitor of phosphate transport. Finally, FGF7 message was confirmed in PCR products of mRNA extracted from fragments of each tumor. Members of the FGF family (other than FGF23) are expressed by OO-associated tumors and may play a role in mediating this syndrome.
Carpenter
Thomas O
TO
Endocrine Sections of the Department of Pediatrics, Yale University School of Medicine, P.O. Box 208064, New Haven, Connecticut 06520-8064, USA. thomas.carpenter@yale.edu
Ellis
Bruce K
BK
Insogna
Karl L
KL
Philbrick
William M
WM
Sterpka
John
J
Shimkets
Richard
R
D000328:Adult; D001859:Bone Neoplasms / Q000503:physiopathology*; D015704:CD4 Antigens / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D017077:Culture Media, Conditioned; D051523:Fibroblast Growth Factor 7; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010018:Osteomalacia / Q000503:physiopathology*; D028061:Phosphate Transport Proteins / Q000037:antagonists & inhibitors*
D015704:CD4 Antigens; D017077:Culture Media, Conditioned; C000717427:FGF23 protein, human; C496453:FGF7 protein, human; D018974:Insulin-Like Growth Factor Binding Protein 4; D028061:Phosphate Transport Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23