Tissue inhibitor of metalloproteinases 3 regulates extracellular matrix - Cell signaling during bronchiole branching morphogenesis
Tissue inhibitor of metalloproteinases 3 regulates extracellular matrix - Cell signaling during bronchiole branching morphogenesis
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DOI：
10.1016/j.ydbio.2006.07.004
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发表时间：
2006-10-15
影响因子：
2.7
通讯作者：
Leco, Kevin J.
中科院分区：
文献类型：
--
作者：
Gill, Sean E.;Pape, M. Cynthia;Leco, Kevin J.
金属蛋白酶组织抑制剂（TIMPs）在胚胎发育过程中通过基质金属蛋白酶（MMPs）调节细胞外基质（ECM）的降解。我们检查了TIMP3缺失小鼠的肺，发现与对照组相比，在整个肺发育过程中，细支气管分支减少，MMPs活性增强，纤连蛋白降解增强。在TIMP3缺失的肺中，粘着斑激酶（FAK）的活化也从胚胎第12.5天到第14.5天减少。在子宫内用合成MMP抑制剂GM6001治疗增强了野生型和无效肺中的分支模式，伴随着纤连蛋白定位的恢复，通过FAK和无效肺中的上皮细胞增殖的信号传导。通过siRNA靶向在WT肺器官培养物中直接下调FAK丰度导致细支气管分支减少，表型模仿TIMP3缺陷。我们认为，在TIMP3不存在的情况下，增强的NIMP活性干扰了局部ECM蛋白水解，扰乱了细支气管分支形态发生期间细支气管树正确模式形成所必需的细胞内信号传导。因此，TIMP3可以通过MMP抑制活性间接调节上皮细胞增殖。虽然其他人已经证明了MMP的这种功能，并且有体外证据表明TIMP 3控制增殖，但据我们所知，这是TIMP 3调节体内增殖的第一个证据。(c)2006年爱思唯尔公司All rights reserved.
Tissue inhibitors of metalloproteinases (TIMPs) regulate extracellular matrix (ECM) degradation by matrix metalloproteinases (MMPs) throughout embryogenesis. We examined lungs from TIMP3 null mice and found decreased bronchiole branching, enhanced activity of MMPs and enhanced fibronectin degradation throughout lung development compared to controls. Activation of focal adhesion kinase (FAK) was also reduced from embryonic days 12.5 through 14.5 in TIMP3 null lungs. Treatment with a synthetic MMP inhibitor, GM6001, in utero enhanced the branching pattern in both wild type and null lungs accompanied by a restoration of fibronectin localization, signaling through FAK and epithelial cell proliferation in null lungs. Direct down-regulation of FAK abundance in WT lung organ culture by siRNA targeting resulted in reduced bronchiole branching, phenocopying the TIMP3 defect. We propose that enhanced NIMP activity in the absence of TIMP3 interferes with focal ECM proteolysis, perturbing the intracellular signaling necessary for correct pattern formation of the bronchiole tree during bronchiole branching morphogenesis. Thus, TIMP3 can indirectly regulate epithelial cell proliferation via MMP inhibitory activity. While others have demonstrated this function for MMPs, and there is in vitro evidence that TIMP3 controls proliferation, to our knowledge this is the first evidence of TIMP3 regulating proliferation in vivo. (c) 2006 Elsevier Inc. All rights reserved.