FGF23—an established master regulator of phosphate metabolism

Relatively recently, FGF23 has been established as the main hormone regulating phosphate metabolism. FGF23, produced in skeletal osteocytes, regulates Pi metabolism through actions in the kidneys. The actions of FGF23 on phosphate balance are to inhibit sodium dependent Pi transport through the NaPi2a (Npt2a/SLC34A1) and NaPi2c (Npt2c/SLC34A3) transporters in the apical membranes of proximal convoluted tubule cells (PCT). This increases Pi excretion. FGF23 binds to FGF receptors (FGFRs) on the basolateral membranes in association with the co-receptor, αklotho. Receptor kinase activation produces a series of phosphorylation events culminating in NHERF-1 phosphorylation, leading to internalization and degradation of NaPi2a. FGF23 also inhibits calcitriol production by PCT cells. Decreased calcitriol inhibits NaPi2b mediated Pi absorption in the proximal small intestine. Other chapters in the book discuss the regulation of FGF23 secretion by osteocytes, but Pi and calcitriol are major factors. In end stage chronic kidney disease, loss of effective FGF23 inhibition of NaPi2a leads to hyperphosphatemia and spiraling but ineffective FGF23 levels.