The role of fibroblast growth factor 23 in renal disease.

Activating mutations in the fibroblast growth factor 23 (FGF23) gene were identified as the cause of autosomal dominant hypophosphataemic rickets (ADHR) [1]. This secreted protein was later shown to play a role in both physiological and pathological phosphate handling. FGF23 may be the key pathogenetic molecule in three different diseases with hypophosphataemia and inappropriate regulation of vitamin D metabolism. In ADHR, the mutations stabilize the FGF23 protein, which leads to increased circulating levels [2]. In X-linked hypophosphataemia (XLH), a disease caused by inactivating mutations of the PHEX gene, the loss of a membrane-bound protease results in increased circulating levels of FGF23 [3]. Also, in the paraneoplastic syndrome of tumour-induced osteomalacia (TIO), tumours secrete large amounts of FGF23 [3–5]. Thus, in three disorders of inorganic phosphate (Pi) wasting, FGF23 circulates in increased amounts, suggesting a pathological role for the molecule. Evidence for a physiological role for FGF23 in Pi handling comes from animal models of altered FGF23 expression. Fgf23 null mice have hyperphosphataemia and increased 1,25(OH)2D3 levels [6], and normal mice treated with Fgf23-blocking antibodies respond by a significant elevation in Pi and 1,25(OH)2D3 levels [7]. Transgenic mice that overexpress FGF23 show a phenotype in concordance with XLH, ADHR and TIO [8–10]. Thus, these animals have reduced serum Pi and 1,25(OH)2D3 levels. Furthermore, FGF23 levels change in response to changes in dietary Pi intake in both rodents and humans [11–13], suggesting a physiological regulation of FGF23 production in response to Pi availability.