Fibroblast growth factor receptor 1c–Fibroblast growth factor 23 complex (FGFR1c–FGF23) (FGFR1c–FGF23)

The Fibroblast growth factor receptor 1c–Fibroblast growth factor 23 (FGFR1c–FGF23) complex is a critical endocrine signaling unit responsible for maintaining systemic phosphate and vitamin D homeostasis (UniProt Q9GZV9, P11362). FGF23, a hormone primarily secreted by osteocytes, binds to the FGFR1c isoform in the kidney, a process that strictly requires the presence of the co-receptor alpha-Klotho to achieve high-affinity binding (Chen et al., 2018, PMID: 29343891). Upon formation, this ternary complex activates downstream MAPK/ERK signaling, which reduces the expression of sodium-phosphate cotransporters in the renal proximal tubules, thereby increasing urinary phosphate excretion (Shimada et al., 2001, PMID: 11533014). It also suppresses the synthesis of active 1,25-dihydroxyvitamin D by inhibiting 1-alpha-hydroxylase and inducing 24-hydroxylase. Pathological overproduction of FGF23 leads to phosphate-wasting diseases such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). In the context of chronic kidney disease, elevated FGF23 levels are linked to left ventricular hypertrophy and increased mortality. The monoclonal antibody Burosumab (Crysvita) targets the FGF23 ligand to prevent its interaction with the FGFR1c–Klotho complex, providing a primary treatment for XLH (FDA, 2018). Additionally, small-molecule FGFR inhibitors can block the receptor's tyrosine kinase activity, though they are typically used in oncology rather than metabolic bone disease.

Other names

FGF23-FGFR1c-Klotho complexFGF23-FGFR1c complexFibroblast growth factor 23-Fibroblast growth factor receptor 1c complexFGF23 signaling complex

Burosumab is a human monoclonal antibody that binds to FGF23 and inhibits its interaction with the FGFR1c-Klotho complex, thereby restoring renal phosphate reabsorption and increasing serum 1,25-dihydroxyvitamin D levels (FDA, 2018). Small molecule FGFR inhibitors like Erdafitinib competitively inhibit the ATP-binding site of the FGFR tyrosine kinase domain, blocking downstream signaling pathways such as MAPK/ERK (PubMed, 29343891).