Plasmin generation dependent on α-enolase-type plasminogen receptor is required for myogenesis
Plasmin generation dependent on α-enolase-type plasminogen receptor is required for myogenesis
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DOI：
10.1160/th03-04-0291
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发表时间：
2003-10-01
影响因子：
6.7
通讯作者：
Muñoz-Cánoves, P
中科院分区：
文献类型：
--
作者：
López-Alemany, R;Suelves, M;Muñoz-Cánoves, P
纤溶酶是一种有效的细胞外蛋白酶，专门降解纤维蛋白（纤维蛋白溶解）。活性纤溶酶是通过尿激酶型纤溶酶原激活剂（uPA）和组织型纤溶酶原激活剂（tRA）对酶原纤溶酶原（猪）的蛋白水解激活而产生的。α-烯醇化酶在几种白细胞类型上构成纤溶酶原的受体，用于定位和促进细胞周纤溶酶原活化。然而，α-烯醇化酶型纤溶酶原受体（PIgR）在肌发生中的作用从未得到证实。在这项研究中，我们表明，C2 C12小鼠成肌细胞表达PIgR，其表达在分化过程中大大诱导。针对PIgR MAb 11 G 1的单克隆抗体具有细胞表面产生的纤溶酶抑制能力，能够在体外完全废除C2 C12成肌细胞融合和分化。此外，纤溶酶活性和PlgR表达在体内再生的骨骼肌中被显著诱导，无论是在实验性损伤的肌肉中还是在mdx小鼠（人杜氏肌营养不良症，DMID的动物模型）的营养不良的肌肉中。mdx肌肉呈现出比人DMD肌肉更好的再生能力和更少的纤维化;因此，mdx肌肉中PIgR/纤溶酶活性的增加表明纤维蛋白溶解系统在mdx再生中的重要贡献。本研究首次表明α-烯醇化酶型纤溶酶原受体是骨骼肌发生的重要组成部分，通过浓缩和增强细胞表面纤溶酶的产生。
Plasmin is a potent extracellular protease specialized in the degradation of fibrin (fibrinolysis). Active plasmin is generated by proteolytic activation of the zymogen plasminogen (Pig) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tRA). alpha-Enolase constitutes a receptor for plasminogen on several leukocyte cell types, serving to localize and promote plasminogen activation pericellularly. However, a role for alpha-enolase-type plasminogen receptor (PIgR) in myogenesis has never been demonstrated. In this study, we show that C2C12 mouse myoblasts express PIgR, being its expression greatly induced during the differentiation process. A monoclonal antibody against PIgR MAb 11G 1, with cell surface-generated plasmin inhibitory abilities, was able to fully abrogate C2C12 myoblast fusion and differentiation in vitro. Moreover, both plasmin activity and PlgR expression were significantly induced in regenerating skeletal muscle in vivo, either in experimentally-injured muscle or in the dystrophic muscle of mdx mouse (an animal model of human Duchenne muscular dystrophy, DMID). The mdx muscle presents better regeneration capacities and less fibrosis than the human DMD muscle; therefore, the increase in PIgR/plasmin activity in mdx muscle suggests an important contribution of the fibrinolytic system in mdx regeneration. This study constitutes the first indication of alpha-enolase-type plasminogen receptor as an important component of skeletal myogenesis, by concentrating and enhancing plasmin generation on the cell surface.