Endocrine Abstracts

The great majority of the phosphorus in the body is found as phosphate (PO₄). Phosphate is critical for the maintenance of bone and skeletal integrity, is a necessary component of important biomolecules, such as RNA and DNA, and is central to signal transduction and cell metabolism. The appropriate serum phosphate concentration is maintained based on the endocrine communication between the skeleton, the kidney, and the intestine. The classical view of phosphate regulation is based on the actions of vitamin D and parathyroid hormone. However, nowadays the fibroblast growth factor (FGF) 23/Klotho axis is recognized as a critical biological system in the regulation of phosphate homeostasis. FGF23 functions as a phosphaturic hormone and also as a counter-regulatory hormone of 1,25(OH)₂D₃. FGF23 is secreted from the bone and acts on the kidney to suppress phosphate reabsorption and 1,25(OH)₂D₃ synthesis, thereby inducing a negative phosphate balance. A critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein, as a co-receptor. Klotho protein forms constitutive binary complexes with the fibroblast growth factor receptors (FGFRs) and increases their binding affinity to and selectivity for FGF23. Without Klotho, FGF23 cannot bind to and activate its cognate FGFRs at physiological concentrations. In addition, there is a soluble form of Klotho with humoral actions. Beyond this physiological role, growing evidence suggest that the FGF23/Klotho system has relevant pathophysiological implications in different clinical processes, including renal phosphate wasting syndromes, chronic kidney disease, secondary hyperparathyroidism, as well as vascular dysfunction, atherosclerosis and cardiovascular morbidity and mortality. Therefore, the components of this new biological system may have great interest as clinical biomarkers, as well as therapeutic targets in these pathological conditions.