FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Area of Science:

• Endocrinology
• Molecular Biology
• Aging Research

Background:

• Transgenic α-Klotho (Kl) mice (KlTg) revealed the antiaging effects of soluble Klotho (sKL130).
• Elevated sKL in humans paradoxically correlates with increased fibroblast growth factor 23 (FGF23), with both membrane KL (mKL135) and sKL130 acting as FGF23 coreceptors.
• The interplay between FGF23, mKL135, and sKL130 in KlTg mice remains unexamined.

Purpose of the Study:

• To investigate the impact of Klotho overexpression on FGF23 levels and signaling pathways in KlTg mice.
• To elucidate the roles of mKL135 and sKL130 in regulating FGF23 expression and function.
• To understand the physiological consequences of elevated FGF23 in the context of Klotho overexpression.

Main Methods:

• Analysis of FGF23 expression and circulating levels in KlTg mice.
• Assessment of hormonal changes, including 1,25(OH)2D and parathyroid hormone.
• Evaluation of physiological outcomes such as hypertension and left ventricular hypertrophy.
• Investigation of FGF23-mediated signaling pathways (ERK, PLC-γ, PI3K/AKT) in the presence of mKL135 and sKL130.

Main Results:

• Membrane Klotho (mKL135), not soluble Klotho (sKL130), stimulated FGF23 expression in osteoblasts, increasing bone and circulating FGF23 levels in KlTg mice.
• Elevated FGF23 suppressed 1,25(OH)2D and parathyroid hormone but did not induce hypophosphatemic rickets.
• KlTg mice exhibited low aldosterone-associated hypertension but not left ventricular hypertrophy.
• mKL135 and sKL130 were essential for FGF23-mediated ERK activation but inhibited FGF23-induced PLC-γ and PI3K/AKT signaling.

Conclusions:

• Klotho overexpression in mice leads to increased FGF23 production, primarily driven by membrane Klotho.
• The FGF23-Klotho axis in KlTg mice modulates hormonal balance and cardiovascular parameters, favoring longevity.
• These findings highlight a complex interaction where FGF23, in the presence of Klotho, biases FGFR signaling pathways, contributing to extended lifespan.