Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.
Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.
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缺乏血小板反应蛋白 2 的小鼠表现出结缔组织异常，这与胶原纤维生成紊乱、血管密度增加和出血素质有关。
DOI：
10.1083/jcb.140.2.419
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发表时间：
1998-01-26
影响因子：
7.8
通讯作者：
Bornstein, P
中科院分区：
文献类型：
--
作者：
Kyriakides, T R;Zhu, Y H;Smith, L T;Bain, S D;Yang, Z;Lin, M T;Danielson, K G;Iozzo, R V;LaMarca, M;McKinney, C E;Ginns, E I;Bornstein, P
血小板反应蛋白（TSP）2及其近亲TSP 1是细胞外蛋白，其功能复杂，了解甚少，且有争议。为了确定TSP 2的功能，我们通过在胚胎干细胞中同源重组来破坏Thbs 2基因，并通过囊胚注射和适当的突变动物繁殖来产生TSP 2缺失小鼠。Thbs 2 −/−小鼠以预期的孟德尔频率产生，表现明显正常，并且具有生育能力。然而，经过仔细检查，这些小鼠显示出各种各样的异常。皮肤胶原纤维排列紊乱，电镜下可见皮肤和肌腱内胶原纤维异常粗大，轮廓不规则。作为这些发现的功能相关性，皮肤脆弱，抗张强度降低，尾巴异常柔韧。突变的皮肤成纤维细胞在附着基质上有缺陷。组织学和定量计算机断层扫描记录了长骨总密度和皮质厚度的增加。突变小鼠也表现出异常的出血时间，用血管性血友病因子抗体染色的小鼠组织的组织学调查显示血管显著增加。TSP 2基因敲除小鼠的不寻常表型的基础可能来自TSP 2可能在皮肤和肌腱中的胶原原纤维形成中发挥的结构作用。然而，这种遗传性疾病的一些不同表现似乎可能是由于TSP 2调节间充质细胞的细胞表面性质的能力，从而影响细胞功能，如粘附和迁移。
Thrombospondin (TSP) 2, and its close relative TSP1, are extracellular proteins whose functions are complex, poorly understood, and controversial. In an attempt to determine the function of TSP2, we disrupted the Thbs2 gene by homologous recombination in embryonic stem cells, and generated TSP2-null mice by blastocyst injection and appropriate breeding of mutant animals. Thbs2−/− mice were produced with the expected Mendelian frequency, appeared overtly normal, and were fertile. However, on closer examination, these mice displayed a wide variety of abnormalities. Collagen fiber patterns in skin were disordered, and abnormally large fibrils with irregular contours were observed by electron microscopy in both skin and tendon. As a functional correlate of these findings, the skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant skin fibroblasts were defective in attachment to a substratum. An increase in total density and in cortical thickness of long bones was documented by histology and quantitative computer tomography. Mutant mice also manifested an abnormal bleeding time, and histologic surveys of mouse tissues, stained with an antibody to von Willebrand factor, showed a significant increase in blood vessels. The basis for the unusual phenotype of the TSP2-null mouse could derive from the structural role that TSP2 might play in collagen fibrillogenesis in skin and tendon. However, it seems likely that some of the diverse manifestations of this genetic disorder result from the ability of TSP2 to modulate the cell surface properties of mesenchymal cells, and thus, to affect cell functions such as adhesion and migration.