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| Klotho基因缺乏型FGF23转基因小鼠生化和骨骼的改变 |
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| Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a klotho-deficient phenotype |
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| Bai X., Dinghong Q., Miao D., Goltzman D., Karaplis A.C. 2009/5/29 18:38:56 |
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American Journal of Physiology - Endocrinology and Metabolism, 2009, Volume 296, Issue 1
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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. |
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| 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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 疾病资源中心
王燕燕 王曙
上海交通大学附属瑞金医院内分泌科
患者，女，69岁。2009年1月无明显诱因下出现乏力，当时程度较轻，未予以重视。2009年3月患者乏力症状加重，尿色逐渐加深，大便习惯改变，颜色变淡。4月18日入我院感染科治疗，诉轻度头晕、心慌，体重减轻10kg。无肝区疼痛，无发热，无腹痛、腹泻、腹胀、里急后重，无恶性、呕吐等。入院半月前于外院就诊，查肝功能：ALT 601IU/L，AST 785IU/L，TBIL 97.7umol/L，白蛋白 41g/L，甲状腺功能：游离T3 30.6pmol/L，游离T4 51.9pmol/L，心电图示快速房颤。
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