Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype
| Autor: | Qiu Dinghong, David Goltzman, Dengshun Miao, Xiuying Bai, Andrew C. Karaplis |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Fibroblast growth factor 23
Genetically modified mouse Male medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism Transgene Acid Phosphatase Mice Transgenic Biology urologic and male genital diseases Fibroblast growth factor Mice Calcitriol Physiology (medical) Internal medicine medicine Animals Klotho Klotho Proteins Crosses Genetic Tartrate-resistant acid phosphatase Glucuronidase Mice Knockout Tartrate-Resistant Acid Phosphatase Phosphorus medicine.disease Alkaline Phosphatase Blotting Northern Phenotype Immunohistochemistry Fibroblast Growth Factors Isoenzymes Fibroblast Growth Factor-23 Endocrinology Parathyroid Hormone Osteomalacia Calcium Female Bone Remodeling Hypophosphatemia |
| Zdroj: | American journal of physiology. Endocrinology and metabolism. 296(1) |
| ISSN: | 0193-1849 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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