Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23.
Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23.
复制标题
DOI：
10.1002/path.2409
复制
发表时间：
2008-11
影响因子：
7.3
通讯作者：
Lanske, B.
中科院分区：
文献类型：
--
作者：
DeLuca, S.;Sitara, D.;Kang, K.;Marsell, R.;Jonsson, K.;Taguchi, T.;Erben, R. G.;Razzaque, M. S.;Lanske, B.
从小鼠（Fgf-23−/−）中基因切除成纤维细胞生长因子23导致寿命短，具有许多异常的生化和形态学特征。这些特征包括脊柱后凸、性腺功能减退和相关的不孕症、骨质减少、肺气肿、严重的血管和软组织钙化以及各种组织的全身萎缩。为了确定Fgf-23−/−小鼠中这些广泛的异常是否可以通过遗传恢复FGF-23的全身作用来改善，我们在2.3 kb α1（I）胶原启动子的控制下，在成骨细胞中产生了表达人FGF-23转基因的Fgf-23−/−小鼠（Fgf-23−/−/hFGF-23-Tg双突变体）。这种新型小鼠模型完全没有内源性FGF-23活性，但在骨细胞中产生人FGF-23，随后释放到循环中。我们的研究结果表明，缺乏Fgf-23活性导致Fgf-23−/−小鼠广泛的早衰样特征和早期死亡，而恢复FGF-23的全身作用可显著改善这些表型，其结果是改善生长，恢复生育力，并显着延长双突变体的生存期。关于它们的血清生化，双突变体逆转了Fgf-23−/−同窝小鼠中发现的严重高磷酸盐血症、高钙血症和高维生素D血症;相反，双突变体显示出与纯FGF-23 Tg小鼠相似的低磷酸盐血症和正常血清1，25-二羟维生素D3水平。与Fgf-23−/−小鼠相比，这些变化与NaPi 2a和1α-羟化酶的肾脏表达减少有关。FGF-23通过全身调节磷酸盐稳态和维生素D代谢来预防广泛的异常特征。这种新的小鼠模型为我们提供了一种体内工具，以研究FGF-23在调节矿物质离子代谢和预防多种异常表型中的全身作用，而不受天然FGF-23的干扰。
Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23−/−) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23−/− mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23−/− mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb α1(I) collagen promoter (Fgf-23−/−/hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23−/− mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23−/− littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D3 levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1α-hydroxylase, compared to Fgf-23−/− mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.
登录
查看更多内容
影响因子：
19.6
作者：
Kazama, JJ;Sato, F;Fukagawa, M
通讯作者：
Fukagawa, M
影响因子：
30.8
作者：
Lorenz-Depiereux, Bettina;Bastepe, Murat;Strom, Tim M.
通讯作者：
Strom, Tim M.
影响因子：
19.6
作者：
Nakanishi, S;Kazama, JJ;Fukagawa, M
通讯作者：
Fukagawa, M
影响因子：
8.2
作者：
Kawaguchi, Hiroshi
通讯作者：
Kawaguchi, Hiroshi
DOI：
10.1152/ajpendo.00008.2006
发表时间：
2006-07-01
影响因子：
5.1
作者：
Liu, Shiguang;Zhou, Jianping;Quarles, L. Darryl
通讯作者：
Quarles, L. Darryl