Klotho–Fibroblast growth factor 23 axis (Klotho–FGF23 axis)

The Klotho–Fibroblast growth factor 23 (FGF23) endocrine axis is a fundamental regulatory system responsible for maintaining phosphate and vitamin D homeostasis (PMID: 18037992). FGF23 is a hormone primarily secreted by osteocytes and osteoblasts in response to high serum phosphate or vitamin D levels (UniProt Q9GZV9). It exerts its biological effects by binding to fibroblast growth factor receptors (FGFRs), specifically requiring the transmembrane protein alpha-Klotho as an essential co-receptor to achieve high-affinity binding in target tissues like the kidney (UniProt Q9UEF7). Activation of this axis in the renal proximal tubule leads to increased phosphate excretion and decreased production of 1,25-dihydroxyvitamin D (PMID: 30030417). Pathological overactivity of the axis, often due to genetic mutations or tumors, results in hypophosphatemic disorders such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (PMID: 29937158). In chronic kidney disease, FGF23 levels rise dramatically to compensate for declining nephron function, but this elevation is associated with adverse outcomes including left ventricular hypertrophy and increased mortality (PMID: 29654215). Therapeutic intervention currently focuses on neutralizing FGF23 with monoclonal antibodies like Burosumab to restore phosphate balance in hypophosphatemic patients (FDA Label). Research is also investigating Klotho supplementation or FGF23 inhibition as potential treatments for the systemic complications of renal failure.

Other names

FGF23-Klotho pathwayFGF23-Klotho systemalpha-Klotho-FGF23 axisFibroblast growth factor 23-Klotho endocrine axis

Monoclonal antibody-mediated neutralization of FGF23 to prevent its binding to the FGFR-Klotho complex, thereby increasing renal phosphate reabsorption and active vitamin D synthesis.