[Regulation of calcium homeostasis by α-Klotho and FGF23]

Abstract

α-klotho was first identified as an aging gene and was later shown to be a regulator of phosphate and vitamin D metabolism, and a regulator of calcium homeostasis. α-kl is expressed in the parathyroid glands, choroid plexus and kidney, where α-Kl binds to Na(+), K(+)-ATPase. Low extracellular calcium concentrations trigger rapid translocation of α-Kl/Na(+), K(+)-ATPase complex from endosomal organella to the plasma membrane. This may lead to the PTH secretion in parathyroid glands and transepithelial transport of calcium in kidney and choroid plexus. FGF members are divided into 7 subfamilies. Among them, metabolic FGF subfamily, consisted of FGF19, FGF21 and FGF23, is characterized as their hormonal effects. Indeed,FGF23 is secreted from bone and is circulated to kidney where FGF23 tranceduces signals that suppress vitamin D synthesis and phosphate reabsorption fgf23 deficient phenotypes were reminiscent of those of mice lacking the α-kl gene, which led us the discovery of molecular interaction and functional crosstalk of α-Kl and FGF23. FGF23 binds to α-Kl and converts the canonical FGF receptor 1c to specific for FGF23 and we proposed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of α-Kl, FGF23, PTH and 1,25 (OH) (2)D. α-Kl and FGF23 are novel regulators that integrate the fields of mineral homeostasis, life-style related diseases and aging. This newly established field is widely and remarkably progressing and expected to be fruitful.