Circulating αKlotho influences phosphate handling by controlling FGF23 production

Area of Science:

• Endocrinology
• Molecular Biology
• Mineral Metabolism

Background:

• Alpha-Klotho (αKL) functions as a coreceptor for FGF23 signaling via FGF receptors (FGFRs).
• αKL exists as membrane-bound (mKL) and circulating (cKL) forms; cKL is a cleavage product of mKL.
• A patient with a KL gene translocation presented with rickets, hypophosphatemia, and elevated FGF23, suggesting a role for cKL in phosphate regulation.

Purpose of the Study:

• To investigate whether circulating alpha-Klotho (cKL) regulates phosphate handling by controlling FGF23 expression.

Main Methods:

• Mice were treated with adeno-associated virus to elevate cKL levels.
• In vitro assays assessed cKL interaction specificity with FGF23 and FGFR dependence.

Main Results:

• Elevated cKL induced dose-dependent hypophosphatemia, hypocalcemia, and markedly increased FGF23 levels (38-456 fold).
• Treated mice developed fractures, reduced bone mineral content, expanded growth plates, and osteomalacia with increased bone Fgf23 mRNA (>150 fold).
• In vitro, cKL specifically interacted with FGF23 in an FGFR-dependent manner.

Conclusions:

• Circulating alpha-Klotho (cKL) potently stimulates FGF23 production in vivo.
• This mechanism explains the phenotype of the KL translocation patient and metabolic bone disorders linked to elevated FGF23.
• Findings highlight cKL's role in regulating phosphate homeostasis and biomineralization.