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- Title
Circulating aKlotho influences phosphate handling by controlling FGF23 production.
- Authors
Smith, Rosamund C.; O'Bryan, Linda M.; bFarrow, Emily G.; Summers, Lelia J.; Clinkenbeard, Erica L.; Roberts, Jessica L.; Cass, Taryn A.; Saha, Joy; Broderick, Carol; Linda Ma, Y.; Qing Qiang Zeng; Kharitonenkov, Alexei; Wilson, Jonathan M.; Qianxu Guo; Haijun Sun; Allen, Matthew R.; Burr, David B.; Breyer, Matthew D.; White, Kenneth E.
- Abstract
The FGF23 coreceptor aKlotho (aKL) 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 aKLOTHO (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 aKL and FGF23 in disorders of phosphate handling and biomineralization.
- Subjects
FIBROBLAST growth factors; GENE expression; PHYSIOLOGICAL effects of phosphates; MEMBRANE proteins; CELLULAR signal transduction; CHROMOSOMAL translocation; HYPOPHOSPHATEMIA
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 12, p4710
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI64986