New insights into phosphate homeostasis: fibroblast growth factor 23 and frizzled-related protein-4 are phosphaturic factors derived from tumors associated with osteomalacia

Purpose of review Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In Hyp mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.