Changes in Dermal Fibroblasts from Abcc6-/- Mice Are Present before and after the Onset of Ectopic Tissue Mineralization
Changes in Dermal Fibroblasts from Abcc6-/- Mice Are Present before and after the Onset of Ectopic Tissue Mineralization
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DOI：
10.1038/jid.2014.88
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发表时间：
2014-07-01
影响因子：
6.5
通讯作者：
Quaglino, Daniela
中科院分区：
文献类型：
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作者：
Boraldi, Federica;Bartolomeo, Angelica;Quaglino, Daniela
弹性假性黄瘤（PXE）是一种由ABCC6基因突变引起的罕见遗传病，其特征是皮肤、眼睛和心血管系统的弹性纤维进行性钙化。矿化的病理机制尚不清楚。已经提出了几个假设，其中一个假设是成纤维细胞在控制钙化细胞外基质的数量和质量方面的作用。这一假设提出了一个问题，即间充质细胞的变化是否是钙化过程的原因和/或后果。在这项研究中，从不同年龄的Abcc6（+/+）和Abcc6（-/-）小鼠中分离并培养成纤维细胞，以研究已知与PXE患者成纤维细胞表型相关的参数。结果表明，在钙化发生之前，已经存在一些变化（Ank和Opn下调）。相比之下，在组织矿化开始后，Abcc6（-/-）小鼠中可以观察到其他参数（细胞内O-2（-）含量、Tnap活性和Bmp2上调）的改变。这些数据表明，在Abcc6（-/-）基因型中，真皮成纤维细胞积极促进促进基质钙化的变化，这些细胞可以随着时间的推移被钙化环境进一步调节，从而促进疾病的年龄依赖性进展。
Pseudoxanthoma elasticum (PXE), a rare genetic disease caused by mutations in the ABCC6 gene, is characterized by progressive calcification of elastic fibers in the skin, eyes, and the cardiovascular system. The pathomechanism of the mineralization is still obscure. Several hypotheses have been proposed, one of them suggesting a role for fibroblasts in controlling the amount and the quality of the calcified extracellular matrix. This hypothesis raises the question whether changes in mesenchymal cells are the cause and/or the consequences of the calcification process. In this study, fibroblasts were isolated and cultured from Abcc6(+/+) and Abcc6(-/-) mice of different ages to investigate parameters known to be associated with the phenotype of fibroblasts from PXE patients. Results demonstrate that a few changes (Ank and Opn downregulation) are already present before the occurrence of calcification. By contrast, a modification of other parameters (intracellular O-2(-) content, Tnap activity, and Bmp2 upregulation) can be observed in Abcc6(-/-) mice after the onset of tissue mineralization. These data suggest that in the Abcc6(-/-) genotype, dermal fibroblasts actively contribute to changes that promote matrix calcification and that these cells can be further modulated with time by the calcified environment, thus contributing to the age-dependent progression of the disease.