Tumor-induced osteomalacia and the regulation of phosphate homeostasis

Tumor-induced osteomalacia (TIO) is a rare and unique syndrome characterized by hypophosphatemia, excessive urinary phosphate excretion, reduced 1,25-dihydroxyvitamin D concentrations, and osteomalacia. Removal of the tumor is associated with a cure of the lesion. Several laboratories have now shown that conditioned medium derived from cultures of such tumors contain a small, heat-sensitive substance (“phosphatonin”) of <25,000 daltons that specifically inhibits sodium-dependent phosphate transport in cultured renal proximal tubular epithelia. This substance does not increase cyclic adenosine monophosphate (cAMP) formation in tubular epithelial cells and does not increase cAMP excretion in urine. A substance with similar properties is present in the circulation of patients on hemodialysis. A syndrome with a remarkably similar biochemical phenotype, namely, X-linked hypophosphatemic rickets (XLH), also has a circulating factor with properties similar, if not identical, to those of the tumor-derived factor, “phosphatonin.” The molecular defect in XLH has been shown to be due to a mutant endopeptidase, PHEX, whose substrate might be “phosphatonin.” Hypophosphatemia and other biochemical abnormalities in TIO are due to excessive production of “phosphatonin” with normal PHEX function, whereas the biochemical abnormalities in XLH are caused by a mutant PHEX enzyme that fails to process “phosphatonin.”