Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K.
Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K.
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DOI：
10.1186/s13104-015-1284-8
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发表时间：
2015-07-29
影响因子：
1.8
通讯作者：
Shastri VP
中科院分区：
文献类型：
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作者：
Christensen J;Shastri VP
基质金属蛋白酶9 （matrix -metalloproteinases 9, MMP-9）是一类基质金属蛋白酶，其主要功能是降解和重塑细胞外基质（extracellular matrix， ECM）。MMP-9已被证明是许多疾病的组成部分，其中ECM的调节是癌症，骨质疏松症和纤维化等关键步骤。MMP-9作为一种潜伏的前酶分泌，需要在细胞外空间激活。因此，确定能够激活MMP-9的生理和分子环境是很重要的。将破骨细胞条件培养基酸化至pH 5，产生一个大小与活性MMP-9相对应的片段。同样，在pH为5的条件下，用重组组织蛋白酶K （CTSK）处理重组proMMP-9，产生了一个与活性MMP-9分子量相对应的片段，并显示出MMP-9的活性。在CTSK抑制剂的存在下，这种激活被取消，表明CTSK负责激活pro-MMP-9。与野生型对照相比，在MDA-MB-231细胞中敲除CTSK也会降低MMP-9的活性。在这里，我们提供了第一个证据，证明CTSK可以在酸性环境中切割和激活MMP-9，例如在肿瘤和骨吸收过程中看到的。这一发现提供了CTSK在肿瘤和骨骼中的表达与通过MMP-9激活的ECM重塑之间的关键联系。本研究阐明了通过胞外生理变化激活MMP-9的新机制，揭示了CTSK和MMP-9参与的蛋白酶信号网络，为探索ECM蛋白酶作为生理标志物和药理靶点提供了动力。本文的在线版本（doi:10.1186/s13104-015-1284-8）包含补充材料，可供授权用户使用。
Matrix-metalloproteinases 9 (MMP-9) belongs to the class of matrix metalloproteinases whose main function is to degrade and remodel the extracellular matrix (ECM). MMP-9 has been shown to be an integral part of many diseases where modulation of the ECM is a key step such as cancer, osteoporosis and fibrosis. MMP-9 is secreted as a latent pro-enzyme that requires activation in the extracellular space. Therefore, identifying physiological and molecular contexts, which can activate MMP-9 is important. Acidification of osteoclast-conditioned media to pH 5 resulted in a fragment with a size corresponding to active MMP-9. Also, treatment of recombinant proMMP-9 with recombinant cathepsin K (CTSK) at pH 5 yielded a fragment that corresponded to the molecular weight of active MMP-9, and showed MMP-9 activity. This activation was abrogated in the presence of CTSK inhibitor indicating that CTSK was responsible for the activation of pro-MMP-9. Knocking down CTSK in MDA-MB-231 cells also diminished MMP-9 activity compared to wild type control. Here we provide the first evidence that CTSK can cleave and activate MMP-9 in acidic environments such as seen in tumors and during bone resorption. This finding provides a key link between CTSK expression in tumors and bone and ECM remodeling, through MMP-9 activation. This novel mechanism to activate MMP-9 through extracellular physiological changes elucidated in this study reveals a protease-signaling network involving CTSK and MMP-9 and provides the impetus to explore ECM proteases as physiological markers and pharmacological targets. The online version of this article (doi:10.1186/s13104-015-1284-8) contains supplementary material, which is available to authorized users.