The mineralization of cartilage and bone matrix requires adequate supplies of calcium and phosphate. Among the causes of defective mineralization of bone (osteomalacia) and defective mineralization of cartilage (rickets) are renal phosphate-wasting disorders that produce hypophosphatemia. Phosphate wasting is either inherited as X-linked hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets, or acquired, as can occur in patients with a variety of benign mesenchymal tumors (hemangiopericytomas, fibromas, angiosarcomas, etc.)(1). Osteomalacia induced by tumors is invariably curable if the tumor can be found and resected, indicating that it has a humoral basis. A paper by Shimada et al.(2) in this issue of PNAS identifies a member of the fibroblast growth factor family, FGF23, as the humoral factor that is secreted by tumors to cause tumorinduced osteomalacia. Shimada et al.(2) cloned cDNAs from a hemangiopericytoma that caused hypophosphatemic osteomalacia (3) and found clones identical to FGF23, which has recently been identified by positional cloning as the gene responsible for autosomal dominant hypophosphatemic rickets (4). When injected into mice, recombinant FGF23 produced mild phosphaturia and hypophosphatemia, but CHO-FGF23 cells, when grown as tumors in nude mice, fully reproduced the human syndrome of severe hypophosphatemia, growth retardation, rickets in the growth plates, deformities of the skeleton, reduced mineralization of bone, and seams of unmineralized osteoid in bone (2). FGF23 was expressed at high levels in the tumor from which it was cloned, and as recently reported by another group, is also expressed at high levels in other tumors associated with acquired osteomalacia (5), but expression is barely detectable in normal tissues [liver, lymph node, thymus, heart, and the ventrolateral thalamic nucleus of the brain (2, 4, 6)], and notably absent in bone and bone cells. At first glance a member of the matrixbinding FGF family is a surprising candidate as a humoral messenger, but FGF23 lacks several residues that are heparanbinding in FGF1 and conserved in other heparin-binding FGFs (7), and hence may be more soluble than other FGFs. With a 72-aa carboxyl-terminal domain not shared by other family members, FGF23 is the largest member of the FGF family. Insight into its function is gained by considering the mutations that cause autosomal dominant hypophosphatemic rickets. All four unrelated families who were studied had missense mutations in one of two closely spaced arginine residues (R176 and R179) that cosegregated with rickets, with two families sharing the same mutation (4). This clustering of missense mutations in a disorder with dominant inheritance strongly suggested they were gain-offunction mutations. It is therefore interesting that Shimada et al., when they expressed FGF23 in CHO cells, found in addition to the mature protein a fragment beginning with S180. The demonstration that R179S180 is a processing site in FGF23 strongly suggests that mutations of the flanking arginines confer a gain of function on FGF23 by blocking its degradation. The cleavage site is at the boundary between the FGF-homologous region and the unique carboxyl terminus. The other piece of the hypophosphatemia puzzle is X-linked hypophosphatemic rickets, the most common inherited disorder of renal phosphate transport. Positional cloning identified mutations that inactivate a gene called PHEX (8), predicted to encode a membrane-associated metalloprotease of the M13 family, which includes neutral endopeptidase 24.11, endothelin-converting enzymes 1 and 2, and the …