Human Fibroblasts with Mutations in COL5A1 and COL3A1 Genes Do Not Organize Collagens and Fibronectin in the Extracellular Matrix, Down-regulate α2β1 Integrin, and Recruit αvβ3 Instead of α5β1 Integrin*
Human Fibroblasts with Mutations in COL5A1 and COL3A1 Genes Do Not Organize Collagens and Fibronectin in the Extracellular Matrix, Down-regulate α2β1 Integrin, and Recruit αvβ3 Instead of α5β1 Integrin*
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DOI：
10.1074/jbc.m312609200
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发表时间：
2004-04
影响因子：
4.8
通讯作者：
N. Zoppi;R. Gardella;A. De Paepe;S. Barlati;M. Colombi
中科院分区：
文献类型：
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作者：
N. Zoppi;R. Gardella;A. De Paepe;S. Barlati;M. Colombi
与对照组相比，分别携带COL5A1和COL3A1基因突变的I型和IV型EDS患者真皮成纤维细胞合成异常的V型和III型胶原(COL)，并显示这些蛋白在细胞外基质中的组织结构缺陷及其功能受体α2β1整合素的高度减少。EDS细胞培养上清液中纤维连接蛋白(FN)水平降低，缺乏FN纤维网络。最后，EDS细胞普遍合成αvβ3整合素而不是α5β1整合素。α-v-β-3整合素分布于整个细胞表面，在纯化的FN作用下表现出FN结合和组装的特性。用纯化的COLLV或COLLIII处理EDS细胞，但不用FN处理，可恢复对照表型(COL+、FN+、αvβ3-、α5β1+、α2β1+)。抗COLLV、COLLIII或α2β1整合素的功能阻断抗体诱导对照成纤维细胞出现EDS样表型(COL-、FN-、αvβ3+、α5β1-、α2β1-)。这些结果表明，在人成纤维细胞中，α2β1整合素的组织和功能由其配体控制，α2β1与COL的相互作用反过来调节FN整合素受体的募集：高水平的α2β1整合素诱导α5β1整合素组织，而低α2β1整合素水平导致αvβ3整合素组织。
Dermal fibroblasts derived from types I and IV Ehlers-Danlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the α2β1 integrin, compared with control fibroblasts. EDS cells also show reduced levels of fibronectin (FN) in the culture medium and lack an FN fibrillar network. Finally, EDS cells prevalently organize αvβ3 integrin instead of α5β1 integrin. The αvβ3 integrin, distributed on the whole EDS cell surface, shows FN binding and assembly properties when the cells are treated with purified FN. Treatment of EDS cells with purified COLLV or COLLIII, but not with FN, restores the control phenotype (COLL+, FN+, αvβ3–, α5β1+, α2β1+). Function-blocking antibodies to COLLV, COLLIII, or α2β1 integrin induce in control fibroblasts an EDS-like phenotype (COLL–, FN–, αvβ3+, α5β1–, α2β1–). These results show that in human fibroblasts α2β1 integrin organization and function are controlled by its ligand, and that the α2β1-COLL interaction, in turn, regulates FN integrin receptor recruitment: high α2β1 integrin levels induce α5β1 integrin organization, while low α2β1 integrin levels lead to αvβ3 integrin organization.