Ming Chang Hu1,2, Mingjun Shi3, Orson W Moe4,5,6. 1. Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. ming-chang.hu@utsouthwestern.edu. 2. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. ming-chang.hu@utsouthwestern.edu. 3. Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. 4. Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. orson.moe@utsouthwestern.edu. 5. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. orson.moe@utsouthwestern.edu. 6. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. orson.moe@utsouthwestern.edu.
Abstract
Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.
Alpha-n class="Gene">Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphatemetabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.
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