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Klotho基因缺乏型FGF23转基因小鼠生化和骨骼的改变

Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a klotho-deficient phenotype
Bai X., Dinghong Q., Miao D., Goltzman D., Karaplis A.C.   |   2009/5/29 18:38:56 
American Journal of Physiology - Endocrinology and Metabolism, 2009   |   Volume 296, Issue 1  |   打印| 推荐给好友
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Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) (FTg) 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 FTg mice and obtained FTg transgenic mice homozygous for the Kl-hypomorphic allele (FTg/Kl-/-). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with FTg, wild-type, and Kl-/- controls. From 4 wk onward, FTg/Kl-/- mice were clearly distinguishable from FTg 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 FTg 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 FTg/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 FTr/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 over-expression to a phenotype consistent with Klotho deficiency. Copyright © 2009 the American Physiological Society.
Correspondence Address: Karaplis, A. C.; Division of Endocrinology, Dept. of Medicine, Davis-Jewish General Hospital, 3755 Cote Ste. Catherine Rd, Montreal, QC, H3T 1E2, Canada; email: akarapli@ldi.jgh.mcgill.ca 
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慢性心衰诊治：规范中求突破
黄峻
2012-2-1
南京医科大学第一附属医院
房颤治疗：手段渐趋丰富 新型治疗药物不断涌现 非药物治疗备受关注
马长生
2012-2-1
首都医科大学附属北京安贞医院
注重老年人群特征 优化管理

刘梅林
2012-2-1
北京大学第一医院老年内科

 
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