The discovery of FGF23—a historic view

Fibroblast growth factor 23 (FGF23) is a hormone made by osteocytes and osteoblasts that plays an important role in regulating phosphate and vitamin D homeostasis. Disordered FGF23 homeostasis is responsible for several hypo- and hyperphosphatemic disorders. Research into the pathogenesis of one of these disorders, Autosomal Dominant Hypophosphatemic Rickets (ADHR), led to the identification of FGF23. We have made tremendous progress in understanding the pathophysiology of both normal phosphate and vitamin D physiology and the pathogenesis of several hypo- and hyperphosphatemic disorders. The hypophosphatemic disorders X-lined hypophosphatemic rickets, ADHR, Autosomal Recessive Hypophosphatemic Rickets, and Tumor-Induced Osteomalacia all result from excessive circulating concentrations of FGF23. Conversely, Familial Tumoral Calcinosis, which is a recessive disorder, results from either a mutation in the FGF23 gene itself or a mutation in the gene coding for GLANT3, an enzyme that O-glycosylates the FGF23 protein to prevent cleavage of the intact, biologically active protein. There is also one reported case of a homozygous mutation in the gene coding for αKlotho, a coreceptor that is necessary for FGF23 to bind its receptor. The improved understanding of the pathophysiologic bases of these diseases has resulted in the development of new treatment approaches aimed at targeting FGF23.