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This Article Full Text Full Text (PDF) All Versions of this Article: 296/1/E79    most recent 90539.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bai, X. Articles by Karaplis, A. C. Search for Related Content PubMed PubMed Citation Articles by Bai, X. Articles by Karaplis, A. C.

Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype

¹Division of Endocrinology, Department of Medicine, and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; ²The Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China; and ³Calcium Research Laboratory, Department of Medicine, McGill University Health Center and McGill University, Montreal, Quebec, Canada

Submitted 24 June 2008 ; accepted in final form 29 October 2008

Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) (F^Tg) exhibit biochemical {hypophosphatemia, phosphaturia, abnormal 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] metabolism} and skeletal (rickets and osteomalacia) abnormalities attributable to FGF23 action. In vitro studies now implicate the aging-related factor Klotho in the signaling mechanism of FGF23. In this study, we used a mouse genetic approach to validate in vivo the pivotal role of Klotho in the metabolic and skeletal derangements associated with FGF23 (R176Q) overexpression. To this end, we crossed mice heterozygous for the hypomorphic Klotho allele (Kl^+/–) to F^Tg mice and obtained F^Tg transgenic mice homozygous for the Kl-hypomorphic allele (F^Tg/Kl^–/–). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with F^Tg, wild-type, and Kl^–/– controls. From 4 wk onward, F^Tg/Kl^–/– mice were clearly distinguishable from F^Tg mice and exhibited a striking phenotypic resemblance to the Kl^–/– controls. Serum analysis for calcium, phosphorus, parathyroid hormone, 1,25(OH)₂D₃, and alkaline phosphatase activity confirmed the biochemical similarity between the F^Tg/Kl^–/– and Kl^–/– mice and their distinctness from the F^Tg controls. The characteristic skeletal changes associated with FGF23 (R176Q) overexpression were also dramatically reversed by the absence of Klotho. Hence the wide, unmineralized growth plates and the osteomalacic abnormalities apparent in trabecular and cortical bone were completely reversed in the F^Tg/Kl^–/– mice. Nevertheless, independent actions of Klotho on bone were suggested as manifested by alterations in mineralized bone, and in cortical bone volume which were observed in both the Kl^–/– and F^Tr/Kl^–/– mutants. In summary, our findings substantiate in vivo the essential role of Klotho in the mechanism of action of FGF23 in view of the fact that Klotho ablation converts the biochemical and skeletal manifestations resulting from FGF23 overexpression to a phenotype consistent with Klotho deficiency.

fibroblast growth factor 23