Browsing by Subject "αKlotho"

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    Circulating αKlotho influences phosphate handling by controlling FGF23 production
    (2012-12) Smith, Rosamund C; O'Bryan, Linda M; Farrow, Emily G; Summers, Lelia J; Clinkenbeard, Erica L.; Roberts, Jessica L; Cass, Taryn A; Saha, Joy; Broderick, Carol; Ma, Y Linda; Zeng, Qing Qiang; Kharitonenkov, Alexei; Wilson, Jonathan M; Guo, Qianxu; Sun, Haijun; Allen, Matthew R.; Burr, David B.; Breyer, Matthew D; White, Kenneth E
    The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.
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    Hypophosphatemic rickets: Revealing Novel Control Points for Phosphate Homeostasis
    (Springer US, 2014-09) White, Kenneth E.; Hum, Julia M.; Econs, Michael J.; Department of Medical & Molecular Genetics, IU School of Medicine
    Rapid and somewhat surprising advances have recently been made towards understanding the molecular mechanisms causing heritable disorders of hypophosphatemia. The results of clinical, genetic, and translational studies have interwoven novel concepts underlying the endocrine control of phosphate metabolism, with far-reaching implications for treatment of both rare, Mendelian diseases as well as common disorders of blood phosphate excess such as chronic kidney disease (CKD). In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone Fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism. These hypophosphatemic disorders, as well as others resulting from independent defects in phosphate transport or metabolism, will be reviewed herein, and implications for emerging therapeutic strategies based upon these new findings will be discussed.