The FGF23 and Klotho system beyond mineral metabolism

FGF23 is a bone-derived hormone that acts primarily on the kidney to induce phosphaturia and suppress synthesis of 1,25-dihydroxyvitamin D₃. The unique feature of FGF23 is that it requires Klotho as an obligate co-receptor. The FGF23–Klotho system has emerged as an endocrine axis indispensable for maintaining phosphate homeostasis. Mineral and bone disorders associated with chronic kidney disease (CKD-MBD) can be viewed as a series of events triggered by a compensatory response of the FGF23–Klotho system to excess phosphate intake relative to the residual nephron number. Furthermore, the fact that disruption of the FGF23–Klotho system causes phosphate retention and a syndrome resembling aging in mammals has led to the notion that phosphate accelerates aging. The aging-like pathology caused by phosphate, or phosphatopathy, may be unique to the higher organisms having the Klotho gene and provides new insights into the molecular mechanism of aging in humans.