Fibroblast growth factor 23–Fibroblast growth factor receptor 1c–alpha-Klotho signaling complex (FGF23–FGFR1c–KL complex)

The Fibroblast growth factor 23–Fibroblast growth factor receptor 1c–alpha-Klotho signaling complex is a specialized ternary assembly that serves as the primary regulator of systemic phosphate and vitamin D metabolism (Kuro-o, M. Nature Reviews Nephrology, 2019). FGF23, a hormone secreted by osteocytes, possesses low intrinsic affinity for its cognate receptors (FGFRs) and requires the transmembrane protein alpha-Klotho to function as a mandatory co-receptor (Chen, G., et al. Nature, 2018). Upon formation of the FGF23–FGFR1c–Klotho complex in the renal proximal tubule, intracellular signaling cascades—primarily the MAPK/ERK pathway—are activated, leading to the internalization of sodium-phosphate cotransporters and the suppression of CYP27B1, the enzyme responsible for activating vitamin D (Shimada, T., et al. J Bone Miner Res, 2004). Pathological overproduction of FGF23 leads to phosphate wasting diseases such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia, while deficiency in any component of the complex results in hyperphosphatemia and accelerated aging phenotypes (Whyte, M. P., et al. Lancet, 2019). Therapeutic strategies targeting this complex include the FDA-approved monoclonal antibody Burosumab, which sequesters FGF23 to prevent complex formation and restore mineral balance in patients with XLH (Carpenter, R. W., et al. NEJM, 2018). Understanding this complex is critical for managing mineral bone disorders and chronic kidney disease complications.

Other names

FGF23-FGFR1c-Klotho complexFGF23-FGFR-Klotho ternary complexFGF23 signaling complexFGF23-FGFR1c-alpha-Klotho complex

Burosumab is a monoclonal antibody that binds to the FGF23 ligand, neutralizing its activity and preventing it from associating with the FGFR1c-Klotho complex. This inhibition prevents the activation of downstream signaling pathways (such as MAPK/ERK) that normally reduce renal phosphate reabsorption and suppress active vitamin D production (Carpenter, R. W., et al. NEJM, 2018).