Is FGF23 the long sought after phosphaturic factor phosphatonin?

Abstract

Genetic defects in familial hypophosphataemias associated with low renal phosphate reabsorption The kidney is the principal organ responsible for phosphate homeostasis. It regulates serum phosphate by modulating phosphate reabsorption. This process takes place in the renal proximal tubule and is regulated by dietary phosphate and PTH. A large amount of evidence designates the sodium-phosphate cotransporter NPT2a activity as the rate limiting and regulated step in phosphate reabsorption w1,2x. Thus, NPT2a has been considered an attractive candidate gene in familial hypophosphataemia associated with low renal phosphate reabsorption. However, no familial hypophosphataemia due to a primary decrease in renal phosphate reabsorption has yet been associated with a defect in the NPT2a gene. X-linked hypophosphataemic rickets (XLH) is associated with mutations in the PHEX gene w3x (Table 1). Mutations in the coding region of the NPT2a gene have been excluded in hereditary hypophosphataemic rickets with hypercalciuria (HHRH) w4,5x (and the gene defect is not yet identified). Mutations in the NPT2a gene have been identified only in unrelated adult patients presenting with hypophosphataemia associated with osteoporosis or renal stone disease (D. Prie ´, unpublished observation). These observations imply that other genes are involved in the regulation of renal phosphate excretion. These genes could encode for as yet unidentified sodium-phosphate cotransporters. Alternatively, products of these genes could directly or indirectly regulate NPT2a activity. Supporting this possibility, experimental and clinical data derived from XLH and one clinically distinct disorder, tumour-induced osteomalacia (TIO), provided evidence for the presence of a novel hormone activity, termed ‘phosphatonin’, that regulates phosphate homeostasis through a PTH-independent mechanism w3,6,7x .I s FGF23—a novel factor independently identified by three groups in the last year w8–10x—the long sought after humoral factor phosphatonin?