Involvement of keratinocyte growth factor (KGF)-KGF receptor signaling in developmental estrogenization syndrome of mouse vagina
Involvement of keratinocyte growth factor (KGF)-KGF receptor signaling in developmental estrogenization syndrome of mouse vagina
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DOI：
10.1007/s00441-004-0980-9
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发表时间：
2004-12-01
影响因子：
3.6
通讯作者：
Mori, T
中科院分区：
文献类型：
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作者：
Masui, F;Matsuda, M;Mori, T
小鼠在新生期体内暴露于雌激素或角质形成细胞生长因子（KGF）导致雌激素非依赖性持续增殖和阴道上皮角化，当动物变成成年。在这里，是否以及如何KGF信号参与雌激素对新生小鼠阴道的影响进行了研究与体外方法。将新生小鼠阴道在含有雌二醇-17 β（E-2）、KGF、抗KGF抗体、KGFR抑制肽和肝素的各种组合的无血清培养基中培养3天，然后移植到卵巢切除的宿主小鼠中35天。用5 μ g/ml E-2或5 μ g/ml KGF培养的阴道上皮厚达皮质厚度，而溶剂处理对照组的上皮保持较薄。E-2效应可被抗KGF抗体或KGFR抑制肽阻断。KGF单独治疗剂量低于500 ng/ml不会引起永久性阴道变化，但这种变化确实发生在肝素加低至10 ng/ml KGF治疗的阴道中。另一方面，肝素抑制雌激素引起的永久性阴道变化。这些结果表明，不可逆的阴道变化是由KGF对发育中的阴道的直接作用引起的，并且小鼠阴道的发育雌激素化综合征是由外源性雌激素增强内源性KGF/ KGFR信号传导引起的。
Exposure of mice to estrogen or keratinocyte growth factor (KGF) in vivo during the neonatal period results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium when the animals become adults. Here, whether and how KGF-signaling is involved in the effects of estrogen on the neonatal mouse vagina were studied with an in vitro method. Newborn mouse vaginae were cultured for 3 days in serum-free medium containing various combinations of estradiol-17beta (E-2), KGF, anti-KGF antibody, KGFR inhibitory peptide and heparin, and then transplanted into ovariectomized host mice for 35 days. The vaginae cultured with 5 mug/ml E-2 or 5 mug/ml KGF had a cornified thick epithelium, while the epithelium of the vehicle-treated controls stayed thin. The E-2 effect was blocked by concurrent treatment with anti-KGF antibody or KGFR inhibitory peptide. KGF treatment alone at doses less than 500 ng/ml did not induce permanent vaginal changes but such changes did occur in vaginae treated with heparin plus as little as 10 ng/ml KGF. On the other hand, heparin inhibited the permanent vaginal changes induced by estrogen. These results suggest that irreversible vaginal changes are induced by the direct action of KGF on the developing vagina and that the developmental estrogenization syndrome of mouse vagina is caused by intensification of endogenous KGF/ KGFR signaling by exogenous estrogen.