Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin

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Abstract
Three hypophosphatemic diseases, X-linked dominant hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO), show very similar clinical features including hypophosphatemia due to renal phosphate wasting. Because of some evidence that XLH and TIO are caused by a humoral mechanism, the presence of a phosphate-regulating hormone, phosphatonin, was hypothesized. The causative factor of TIO has been thought to be a strong candidate for phosphatonin. In this review, we summarize recent findings concerning a humoral factor which causes TIO, and discuss the nature of phosphatonin. The PHEX gene and fibroblast growth factor (FGF)-23 were identified as responsible genes for XLH and ADHR, respectively. In addition, FGF-23 was cloned as a gene abundantly expressed in a responsible tumor for TIO and was shown to reproduce almost all characteristics of TIO when overexpressed in mice. Furthermore, FGF-23 was proteolytically processed between Arg179 and Ser180, and all mutations found in ADHR existed in this proteolytic consensus site. Mutant FGF-23 proteins were resistant to the processing and seem to have somehow increased biological activity. There is not yet enough evidence that FGF-23 is phosphatonin, and the relation between PHEX and FGF-23 is unclear. FGF-23 plays important roles in the development of hypophosphatemic diseases. These findings will certainly contribute to the development of new diagnostic and therapeutic maneuvers for hypophosphatemic diseases.