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

The Fibroblast growth factor 23–Fibroblast growth factor receptor complex (FGF23–FGFR complex) is a specialized endocrine signaling assembly that plays a pivotal role in maintaining systemic phosphate homeostasis and mineral metabolism [UniProt Q9GZV9]. FGF23 is a bone-derived hormone that requires the presence of the transmembrane protein alpha-Klotho as an obligate co-receptor to bind with high affinity to its cognate receptors, primarily FGFR1c, FGFR3c, and FGFR4, in the kidney and parathyroid glands [Nature 2018, 553:449-456]. Upon activation, this complex inhibits renal phosphate reabsorption by downregulating sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) and reduces the synthesis of 1,25-dihydroxyvitamin D by suppressing 1-alpha-hydroxylase expression [J Clin Invest 2001, 108:1861-1871]. Pathological overproduction of FGF23 leads to disorders such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia, characterized by severe phosphate wasting and impaired bone mineralization [Nat Rev Nephrol 2019, 15:435-455]. Conversely, deficient FGF23 signaling results in hyperphosphatemia and ectopic calcification [J Clin Endocrinol Metab 2003, 88:4488-4494]. The complex is a validated therapeutic target, with the monoclonal antibody Burosumab designed to bind FGF23 and neutralize its activity, thereby restoring normal phosphate levels in patients with FGF23-mediated hypophosphatemia [N Engl J Med 2018, 378:2098-2106].

Other names

FGF23-FGFR-Klotho complexFGF23 signaling complexFibroblast growth factor 23–Fibroblast growth factor receptor–alpha-Klotho complex

Burosumab is a monoclonal antibody that binds to FGF23 and inhibits its signaling through the FGFR–alpha-Klotho complex, thereby increasing renal phosphate reabsorption and serum 1,25-dihydroxyvitamin D levels.