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

Autor: Xiuying Bai, Qiu Dinghong, Dengshun Miao, Goltzman, David, Karapils, Andrew C.
Předmět:
Zdroj: American Journal of Physiology: Endocrinology & Metabolism; Jan2009, Vol. 296, pE79-E88, 10p, 5 Black and White Photographs, 2 Graphs
Abstrakt: Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) (FT~) exhibit biochemical {hypophosphatemia, phosphaturia, abnormal 1,25-dihydroxyvitamin D3 [l,25(OH)2D31 metabolism) and skeletal (rickets and osteomalacia) abnormalities attributable to FGF23 action. In vitro studies now implicate the aging-related factor Kiotho 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 (R 176Q) overexpression. To this end, we crossed mice heterozygous for the hypomorphic Kiotho allele (Kl+1-) to FTg mice and obtained FTg transgenic mice homozygous for the Kl-hypomorphic allele (FTg/Kl-1-). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with pTg, wild-type, and Kl+1- controls. From 4 wk onward,FTg/Kl-1- mice were clearly distin- guishable from FTX mice and exhibited a striking phenotypic resem- blance to the Kl+1- controls. Serum analysis for calcium, phosphorus, parathyroid hormone, l,25(OH)2D3, and alkaline phosphatase activity confirmed the biochemical similarity between the FTg/Kl-1- and Kl+1- mice and their distinctness from the pTs controls. The characteristic skeletal changes associated with FGF23 (RI 76Q) overexpression were also dramatically reversed by the absence of Kiotho. Hence the wide, unmineralized growth plates and the osteomalacic abnor- malities apparent in trabecular and cortical bone were completely reversed in the FTg/Kl-1--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+1- and FTr/Kl-1- 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 over- expression to a phenotype consistent with Klotho deficiency. [ABSTRACT FROM AUTHOR]
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