Possible Roles of Fibroblast Growth Factor 23 in Developing X-Linked Hypophosphatemia

Abstract

Fibroblast growth factor 23 (FGF23) was identified as a causative factor of autosomal dominant hypophosphatemic rickets (ADHR) and tumor-induced osteomalacia (TIO). Continuous administration of FGF23 by transplanting the FGF23-expressing CHO cells reproduced typical features observed in TIO patients, such as hypophosphatemia, low serum 1,25-dihydroxyvitamin D level, and osteomalacia in nude mice. A series of in vivo studies have shown that FGF23 can reduce sodium dependent phosphate co-transporter (NaPi2a) protein amount and 1α-hydroxylase mRNA level, and increase 24-hydroxylase mRNA levels in kidney. Fgf23 knockout mice demonstrated severe hyperphosphatemia, significant elevation in serum 1,25-dihydroxyvitamin D level and abnormal skeletal development. In addition, vitamin D treatment or dietary phosphate loading have been shown to stimulate FGF23 production. These evidences suggest that FGF23 plays an essential role in regulating phosphate and vitamin D metabolisms in normal physiology. On the other hand, the elevation of serum FGF23 levels in patients with X-linked hypophosphatemic rickets (XLH) has suggested important roles of FGF23 in developing XLH as well as ADHR and TIO. In our recent preliminary study, administration of anti-FGF23 neutralizing antibody ameliorated hypophosphatemia and rachitic bone characters in Hyp mice. These findings indicate a pathological contribution of FGF23 in development of XLH and may provide new insights to its therapy.