Fibroblast growth factor 23, klotho and heparin

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that regulates phosphate and vitamin D metabolism by targeting the kidney. When highly elevated, such as in chronic kidney disease (CKD), FGF23 can also target the heart and induce pathologic remodeling. Here we discuss the mechanisms that underlie the physiologic and pathologic actions of FGF23, with focus on its FGF receptors (FGFR) and co-receptors.

Klotho is a transmembrane protein that acts as an FGFR co-receptor for FGF23 on physiologic target cells. Klotho also exists as a circulating variant, and recent studies suggested that soluble klotho (sKL) can mediate FGF23 effects in cells that do not express klotho. Furthermore, it has been assumed that the actions of FGF23 do not require heparan sulfate (HS), a proteoglycan that acts as a co-receptor for other FGF isoforms. However, recent studies revealed that HS can be part of the FGF23:FGFR signaling complex and modulate FGF23-induced effects.

sKL and HS have appeared as circulating FGFR co-receptors that modulate the actions of FGF23. Experimental studies suggest that sKL protects from and HS accelerates CKD-associated heart injury. However, the in vivo relevance of these findings is still speculative.