ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release
ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release
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DOI：
10.1073/pnas.1319582110
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发表时间：
2013-12-10
影响因子：
11.1
通讯作者：
van de Wetering, Koen
中科院分区：
文献类型：
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作者：
Jansen, Robert S.;Kucukosmanoglu, Asli;van de Wetering, Koen
弹性纤维性假黄瘤（PXE）是一种常染色体隐性遗传疾病，其特征是皮肤、眼睛和动脉的进行性异位矿化，目前尚无有效的治疗方法。PXE是由编码ATP结合盒亚家族C成员6（ABCC 6）的基因失活突变引起的，ABCC 6是一种主要存在于肝脏中的ATP依赖性外排转运蛋白。Abcc 6（-/-）小鼠有助于证明PXE是一种由循环中缺乏未知因素引起的代谢疾病，该因素的存在取决于肝脏中的ABCC 6。为什么缺乏这个因素导致PXE仍然是一个谜。在这里，我们报告说，从HEK 293细胞过度表达人或大鼠ABCC 6的培养基有效地抑制体外矿化，而从HEK 293对照细胞的培养基没有。非靶向代谢组学显示，表达ABCC 6的细胞分泌大量的核苷三磷酸，即使ABCC 6本身不运输核苷三磷酸。在细胞外，外核苷酸酶将分泌的核苷三磷酸水解为核苷一磷酸和无机焦磷酸（PPi），PPi是一种强的矿化抑制剂，在类似于PXE的几种矿化障碍中起着关键作用。我们的数据的体内相关性在Abcc 6（-/-）小鼠中得到证实，其血浆PPi水平<WT小鼠中发现的血浆PPi水平的40%。这项研究提供了ABCC 6如何影响PXE的见解。我们的数据表明，通常防止PXE的因素是PPi，这是通过一个尚未确定的，但ABCC 6依赖性机制提供给循环的形式核苷三磷酸。
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATP-binding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6(-/-) mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6(-/-) mice, which had plasma PPi levels < 40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an asyet unidentified but ABCC6-dependent mechanism.