11 FGF-23 is a 251 amino acid protein that is predominantly synthesized and secreted by cells from an osteoblast lineage,12,13 and has an estimated half-life in the circulation

of 58 min.14 FGF-23 can be detected with an enzyme-linked immunosorbent assay, in which antibodies detect N-terminal and C-terminal portions. An alternative C-terminal assay recognizes only the C-terminal fragments selleck products of active and inactive FGF-23.15 Early debate focused on whether the circulating FGF-23 is biologically active or whether the available assays also detect inactive compounds. A recent study compared the immune-based and intact FGF-23 assays with an assessment of FGF-23 bioactivity and western blot characterization of circulating FGF-23.16 The assays strongly correlated with each other and with FGF-23 bioactivity. The western blot detected only intact FGF-23 suggesting that virtually all circulating FGF-23 is biologically active. About 80% of total body phosphate is present in bone, 9% in skeletal muscle and only 0.1% in extracellular fluid.17 The distal duodenum is responsible for most phosphate absorption, a process actively mediated by calcitriol.18,19 In the kidneys about 95% of filtered phosphate is reabsorbed in the proximal tubular cells, a process driven by a high extracellular sodium gradient that is actively maintained

by a Na+-K+-ATPase.18 This is further facilitated by Na-P co-transporters on the luminal side of the tubular cells, which are modulated by parathyroid hormone (PTH) and calcitriol.20 FGF-23 induces phosphaturia by reducing the number selleck screening library of co-transporters on the renal tubular cells, as well as mitigating the effects of calcitriol on intestinal absorption.21 Leukocyte receptor tyrosine kinase PTH can stimulate phosphaturia in a similar manner; however, studies from transgenic mice suggest that FGF-23 induced phosphaturia is not PTH dependent.22 The biological effects of FGF-23 are exerted through activation of FGF receptors (FGF-R). Klotho is a trans-membrane

protein originally described in mice with a phenotype of accelerated ageing and atherosclerosis.23 Klotho directly interacts with FGF-R, allowing it to bind FGF-23 with a higher affinity and increased specificity.13,24 The activation of FGF-R therefore occurs in a Klotho-dependent manner.24 Klotho-deficient mice manifest a similar phenotype to FGF-23 deficient mice despite high circulating levels of the FGF-23.8 The tissue selectivity of FGF-23 may be conferred by Klotho expression in the renal tubule and parathyroid glands.25 The expression of FGF-R and Klotho in the parathyroid glands also supports a regulatory effect of FGF-23 on PTH secretion.26 The main known physiological role of FGF-23 is to regulate urinary phosphate excretion and maintain a stable serum phosphate (Fig. 1).27 An important secondary role is the counter-regulation (against PTH) of vitamin D biosynthesis.