What is FGF23 and what does it do?
The kidney sets the phosphate balance by how much phosphate it reabsorbs in the proximal convoluted tubule, so the body needs a signal that tells the kidney when phosphate is too high. That signal is FGF23, a hormone of the FGF19 family. It is produced mainly by bone cells, in particular osteoblasts and osteocytes. Because it is made in bone and acts at a distance, the skeleton can report its own mineral load to the kidney and the gut.
The main job of FGF23 is to lower phosphate. It does this at two ends of the balance at once: it removes phosphate through the urine, and it reduces phosphate uptake from the gut. Both effects move phosphate in the same direction, down, so they add up. FGF23 also restrains calcitriol, the active form of vitamin D, and that restraint is how it reaches the gut.
How does it act on the kidney and the gut?
If one hormone lowers phosphate at both ends, each end has its own change. In the kidney, FGF23 promotes phosphorus excretion. It does so by down-regulating the phosphorus transporters in the proximal convoluted tubule (PCT), so fewer transporters are left in the tubule cells to take phosphate back, and more of it stays in the urine. FGF23 also inhibits the formation of calcitriol in the kidney.
The second effect is in the intestine, where FGF23 reduces phosphorus absorption. This is largely because the fall in calcitriol removes the signal that drives intestinal phosphate absorption. The gut effect therefore follows largely from the effect on calcitriol.
What lets cells respond to FGF23?
Both actions need a receptor on the target cell. The FGF23 receptor is an IG-like domain-containing receptor with three IG-like parts. It belongs to the FGFR (fibroblast growth factor receptor) family, which are tyrosine kinase receptors.
The receptor does not work alone. The Klotho domain is an important co-receptor for FGFR, and Klotho plays an important role in the activation and signal transduction of FGF23. Without Klotho, FGF23 cannot exert its phosphate-lowering effect.
How is active FGF23 made and kept?
The receptor responds to the active hormone, so the next question is how the body makes it. The first protein product of the FGF23 gene is a pre-protein of 251 amino acids. This is cleaved into an N-terminal core and a smaller C-terminal part, and the two parts together make active FGF23.
Active FGF23 is extensively O-glycosylated, and this makes it resistant to proteolysis, so the active form can survive in the blood. Proteolysis still happens, and the fragments it makes are physiological antagonists of the active molecule.
What releases FGF23?
A hormone this powerful needs triggers. FGF23 is released in response to high phosphate, which is a negative feedback loop, because FGF23 then lowers phosphate. It is also released in response to high PTH, which experimental studies suggest, and to high calcitriol.
Iron deficiency increases FGF23 expression too. This increase is mostly devoted to carboxy-terminal FGF23 (cFGF23).
Calcitriol is the partner in this loop. It drives FGF23 release, and FGF23 in turn restrains calcitriol, so each hormone limits the other’s effect. Calcitriol synthesis, activation and regulation are the remaining piece of the axis. How is calcitriol itself made, and what does it do to calcium and phosphate?