FGF23 and Disorders in Phosphate Metabolism

Serum phosphate level is maintained within rather narrow range although the precise mechanism of this regulation of serum phosphate level has just begun to be clarified. Chronic hypophosphatemia results in impaired mineralization of hard tissues. Investigation of pathophysiology of several hypophosphatemic diseases identified fibroblast growth factor (FGF)23 as a novel phosphate-regulating humoral factor. There are three kinds of hypophosphatemic rickets/osteomalacia that share common clinical features. Those are two inherited diseases called autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and X-linked hypophosphatemic rickets/osteomalacia (XLH), and one acquired paraneoplastic syndrome named tumor-induced rickets/osteomalacia (TIO). These diseases are characterized by hypophosphatemia due to impaired renal proximal tubular phosphate reabsorption. FGF23 was positionally cloned as a responsible gene for ADHR and several mutations in FGF23 gene were identified in patients with ADHR. Almost simultaneously, FGF23 was also identified as a causative factor for TIO. Furthermore, increased serum level of FGF23 was reported in patients with TIO and XLH. Recombinant FGF23 decreased serum phosphate at least in part by suppressing expression level of type 2a sodium-phosphate cotransporter that is believed to mediate physiological phosphate reabsorption in proximal tubules. These results indicate that excess action of FGF23 results in hypophosphatemia by suppressing reabsorption of phosphate. In contrast, knockout mice for FGF23 exhibited hyperphosphatemia due to enhanced reabsorption of phosphate in proximal tubules. Furthermore, it was shown that deficient action of FGF23 due to mutations in FGF23 gene results in tumoral calcinosis characterized by hyperphosphatemia in human. These results indicate that FGF23 is an indispensable humoral factor for maintaining serum phosphate level. Modulation of FGF23 activity may be a new therapeutic way for disorders with deranged mineral metabolism.