Complementary roles of intracellular and pericellular collagen degradation pathways in vivo
Complementary roles of intracellular and pericellular collagen degradation pathways in vivo
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DOI：
10.1128/mcb.00291-07
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发表时间：
2007-09-01
影响因子：
5.3
通讯作者：
Holmbeck, Kenn
中科院分区：
文献类型：
--
作者：
Wagenaar-Miller, Rebecca A.;Engelholm, Lars H.;Holmbeck, Kenn
胶原蛋白降解对细胞迁移、增殖和分化至关重要。胶原蛋白的两个关键转化途径是：细胞内组织蛋白酶介导的降解和细胞外胶原酶介导的降解。然而，这两种途径之间的功能关系尚不清楚，甚至存在争议。在这里，我们表明细胞内和细胞周围胶原转换途径在体内具有互补的作用。细胞内胶原降解（尿激酶纤溶酶原激活物受体相关蛋白/Endo180消融）或细胞外胶原降解（膜型1-基质金属蛋白酶消融）的个体缺陷与发育和生存是相容的。然而，它们的综合缺陷通过严重损害骨形成而协同导致出生后死亡。有趣的是，这与软骨和骨形成细胞在其富含胶原的微环境中增殖失败和生存不良有机制联系。这些发现对于使用胶原酶活性的药理学抑制剂来预防各种疾病中的结缔组织破坏具有重要意义。
Collagen degradation is essential for cell migration, proliferation, and differentiation. Two key turnover pathways have been described for collagen: intracellular cathepsin-mediated degradation and pericellular collagenase-mediated degradation. However, the functional relationship between these two pathways is unclear and even controversial. Here we show that intracellular and pericellular collagen turnover pathways have complementary roles in vivo. Individual deficits in intracellular collagen degradation (urokinase plasminogen activator receptor-associated protein/Endo180 ablation) or pericellular collagen degradation (membrane type 1-matrix metalloproteinase ablation) were compatible with development and survival. Their combined deficits, however, synergized to cause postnatal death by severely impairing bone formation. Interestingly, this was mechanistically linked to the proliferative failure and poor survival of cartilage- and bone-forming cells within their collagen-rich microenvironment. These findings have important implications for the use of pharmacological inhibitors of collagenase activity to prevent connective tissue destruction in a variety of diseases.