Circulating αKlotho influences phosphate handling by controlling FGF23 production

Rosamund C. Smith, Linda M. O'Bryan, Emily G. Farrow, Lelia J. Summers, Erica L. Clinkenbeard, Jessica L. Roberts, Taryn A. Cass, Joy Saha, Carol Broderick, Y. Linda Ma, Qing Qiang Zeng, Alexei Kharitonenkov, Jonathan M. Wilson, Qianxu Guo, Haijun Sun, Matthew R. Allen, David B. Burr, Matthew D. Breyer, Kenneth E. White

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4710-4715
Number of pages6
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Smith, R. C., O'Bryan, L. M., Farrow, E. G., Summers, L. J., Clinkenbeard, E. L., Roberts, J. L., Cass, T. A., Saha, J., Broderick, C., Ma, Y. L., Zeng, Q. Q., Kharitonenkov, A., Wilson, J. M., Guo, Q., Sun, H., Allen, M. R., Burr, D. B., Breyer, M. D., & White, K. E. (2012). Circulating αKlotho influences phosphate handling by controlling FGF23 production. Journal of Clinical Investigation, 122(12), 4710-4715. https://doi.org/10.1172/JCI64986