Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum
Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum
复制标题
DOI：
10.1093/hmg/ddi183
复制
发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Bergen, AAB
中科院分区：
文献类型：
--
作者：
Gorgels, TGMF;Hu, XF;Bergen, AAB
弹性假黄瘤(PXE)是一种遗传性结缔组织疾病，主要影响皮肤、眼睛和心血管系统。PXE以弹性纤维营养不良矿化为特征。这种情况是由ABCC6功能突变的丧失引起的。我们通过传统的基因打靶方法获得了Abcc6缺陷小鼠(Abcc6(-/-))。如光学和电子显微镜所示，abcc6(-/-)小鼠自发地在血管壁和眼睛的Bruchs膜中形成弹性纤维的钙化。真皮细胞外基质未见明显异常。血管钙化最明显的是肾皮质的小动脉，但在老年小鼠的其他器官以及主动脉和下腔静脉也发生了钙化。新研制的抗小鼠Abcc6单抗可将该蛋白定位于肝细胞基底膜和肾近端小管的基底膜，但不能在致病部位显示该蛋白。Abcc6(-/-)小鼠的血浆高密度脂蛋白胆固醇降低了25%，血浆肌酐水平升高，这可能是由于肾功能受损所致。血清矿物质平衡未见明显变化。我们的结论是，Abcc6(-/-)小鼠的表型与人类PXE病理中弹性纤维的钙化相似，这使得该模型成为进一步研究PXE病因学的有用工具。我们的数据支持PXE实际上是一种系统性疾病的假设。
Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue, affecting mainly skin, eye and the cardiovascular system. PXE is characterized by dystrophic mineralization of elastic fibres. The condition is caused by loss of function mutations in ABCC6. We generated Abcc6 deficient mice (Abcc6(-/-)) by conventional gene targeting. As shown by light and electron microscopy Abcc6(-/-) mice spontaneously developed calcification of elastic fibres in blood vessel walls and in Bruch's membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Newly developed monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6(-/-) mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. We conclude that the phenotype of the Abcc6(-/-) mouse shares calcification of elastic fibres with human PXE pathology, which makes this model a useful tool to further investigate the aetiology of PXE. Our data support the hypothesis that PXE is in fact a systemic disease.