Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy of Hyp Mice
Elevated Fibroblast Growth Factor 23 Exerts Its Effects on Placenta and Regulates Vitamin D Metabolism in Pregnancy of Hyp Mice
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DOI：
10.1002/jbmr.2186
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发表时间：
2014-07-01
影响因子：
6.2
通讯作者：
Michigami, Toshimi
中科院分区：
文献类型：
--
作者：
Ohata, Yasuhisa;Yamazaki, Miwa;Michigami, Toshimi
成纤维细胞生长因子23(FGF23)以内分泌方式发挥作用，需要α-Klotho对靶器官发挥作用。我们最近证明，人类胎盘也表达a-Klotho，这使我们假设FGF23可能对胎盘起作用。免疫组织化学分析表明，FGFR1和α-Klotho在正常足月胎盘胎母界面均有表达，提示这些区域可能与FGF23有关。因此，我们接下来使用循环中FGF23水平高的Hyp小鼠来研究FGF23是否在胎盘中发挥某些作用。将Hyp和野生型(WT)雌蜂与野生型雄蜂交配，并对其母体和雄体进行分析。HYP母亲FGF23水平升高。Hyp胎儿的FGF23水平大约是Hyp母亲的20倍，而来自Hyp母亲的WT胎儿的FGF23水平较低，来自WT母亲的胎儿也是如此。我们对胎盘基因的表达进行了分析，发现肾脏中FGF23的靶基因--25OHD-24-羟基酶的编码基因CYP24A1在Hyp母亲的胎盘中的表达高于WT母亲的胎盘。在WT胎盘的器官培养中，用Hyp母亲的血浆处理显著增加了CYP24A1的表达，这种表达可被同时加入抗FGF23中和抗体所取消。WT胎盘直接注射重组FGF23可诱导细胞色素P24A1的表达。妊娠期高血压孕妇胎盘组织中细胞色素P24A1的表达增加，导致血浆25-羟基维生素D水平降低。这些结果表明，在病理条件下，如Hyp小鼠，循环中FGF23水平的增加直接影响胎盘，并通过调节CYP24A1的表达来影响胎儿维生素D代谢。(C)2014年美国骨与矿物研究学会。
Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires a-Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses a-Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of a-Klotho in the feto-maternal interface of both mouse and human normal-term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild-type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20-fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD-24-hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti-FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25-hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. (C) 2014 American Society for Bone and Mineral Research.