Chapter 23 - Regulation of phosphate in health and disease

Abstract

Phosphorus (usually as phosphate) is an essential nutrient used for enzyme activation and the synthesis of adenosine triphosphate and other biomolecules. Most phosphorus in the body is sequestered in mineralized bone tissue and teeth. Phosphate homeostasis is maintained by FGF23 derived from bones and the kidney-derived cofactor Klotho. FGF23 binds the membrane-bound Klotho–FGF receptor complex with much higher affinity than the FGF receptor (FGFR) alone to generate downstream signaling events. Aberrations in FGF23, FGFR, or Klotho structure or expression result in dysregulation of serum phosphate levels in experimental animal models and human diseases. The FGF23–Klotho system suppresses sodium-phosphate cotransporters (NaPi2 family proteins) in proximal tubular epithelial cells in the kidney to induce urinary phosphate wasting. In addition, the FGF23–Klotho system also regulates vitamin D metabolism, which is an important factor that regulates the homeostasis of minerals such as calcium, phosphorus, and magnesium. FGF23 can reduce the activity of 1,25-dihydroxyvitamin D3 by increasing the synthesis of the catabolic enzyme 24-hydroxylase and by suppressing renal 1-α hydroxylase expression. Determination of FGF23 or Klotho status may aid in the diagnosis and prognosis of diseases associated with abnormal phosphate levels such as chronic kidney disease, cardiac dysfunction, and bone mineralization defects. Preclinical and clinical studies suggest that dietary phosphate overload has toxic and prolonged adverse health effects. There are pharmaceuticals and biomedical devices to mitigate absorption (or reabsorption) of phosphate from food (or blood) into the body, but these strategies have limited efficacy. Without measures in place to reduce dietary phosphate intake, the conditions associated with phosphate toxicity will likely become a global health concern.