Fibroblast growth factor 23–fibroblast growth factor receptor complex (FGF23–FGFR complex)

The Fibroblast growth factor 23–fibroblast growth factor receptor complex is a multimeric signaling assembly primarily comprising FGF23, an endocrine hormone, FGFR1c (a receptor tyrosine kinase), and the co-receptor α-Klotho[3][1][2][5][7]. FGF23 is secreted mainly by osteocytes and regulates phosphate and vitamin D metabolism by suppressing phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis in the kidney. For high-affinity signaling, FGF23 binds the extracellular domain of FGFR1c in the presence of α-Klotho, which functions as a scaffold, stabilizing the FGF23–FGFR1c interaction and determining tissue specificity through its restricted expression in distal renal tubules[3][7][5]. The canonical pathway involves activation of downstream RAS/RAF/MEK/ERK signaling, leading to phosphate balance control[2][4]. Pathologically elevated FGF23 signaling is implicated in chronic kidney disease–associated cardiovascular disease and hypophosphatemic osteomalacia, whereas loss of function causes hyperphosphatemia. Drugs like Burosumab inhibit FGF23 activity to treat diseases of phosphate wasting by targeting and neutralizing the hormone's interaction with the FGFR–Klotho complex. Safety considerations include the danger of excessive serum phosphate resulting in vascular calcifications, particularly when the axis is over-inhibited[1][7][2][4]. The FGF23–FGFR complex (with Klotho) is a well-established therapeutic target and a biomarker for interventions modulating phosphate and vitamin D homeostasis.

Other names

FGF23–FGFR1c–Klotho complexFGF23–FGFR–Klotho ternary complex

Inhibition of FGF23 binding to FGFR–Klotho complex (e.g., by Burosumab or related agents) - Peptide antagonism/competition for FGF23 binding site (e.g., C-terminal tail peptides)