Dozier S, Escobar G P, Lindsey M L
Cardiology Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7872, San Antonio, TX 78229-3900, USA.
Med Chem. 2006 Sep;2(5):523-6. doi: 10.2174/157340606778250261.
Matrix Metalloproteinases (MMPs) are a class of zinc-dependent enzymes that degrade extracellular matrix components, particularly collagen. MMPs have been implicated in a diverse list of pathological processes, including cancer and cardiovascular disease. Recent efforts to bring MMP inhibitors to clinical trials, however, have proved disappointing. These failures are attributed, in part, to the non-selective nature of current inhibitors. The possibility also exists, however, that inhibition of a particular MMP type will lead to feedback accumulation of parallel MMP members. MMP-7, also known as matrilysin, has a broad list of substrates, including denatured collagen and other MMPs involved in the collagenolytic pathway, namely MMP-1, MMP-2, and MMP-9. Whether the additional collagenases, MMP-8 and MMP-13, are also activated by MMP-7 has not been explored. We show here that recombinant active MMP-7 was able to process MMP-8 to its active form in vitro, but did not activate MMP-13. In the left ventricles of mice lacking the MMP-7 gene, MMP-8 levels increased while MMP-13 levels decreased in vivo. The switch in MMP profile was not accompanied by a change in left ventricular dimensions or wall thickness. Together, these data suggest that MMP-8 is an in vivo substrate of MMP-7, and that the accumulation of pro-MMP-8 in the absence of MMP-7 downregulates pro-MMP-13 levels in order to maintain baseline collagenolytic function. The interplay between MMP-8 and MMP-13 suggest that these MMPs may play reciprocal roles. The design of selective MMP inhibitors, therefore, must take into consideration changes in parallel MMP types as a potential compensatory mechanism.
基质金属蛋白酶（MMPs）是一类锌依赖性酶，可降解细胞外基质成分，尤其是胶原蛋白。MMPs与多种病理过程有关，包括癌症和心血管疾病。然而，最近将MMP抑制剂带入临床试验的努力证明令人失望。这些失败部分归因于当前抑制剂的非选择性性质。然而，也有可能抑制特定类型的MMP会导致平行MMP成员的反馈积累。MMP-7，也称为基质溶素，有大量底物，包括变性胶原蛋白和参与胶原降解途径的其他MMPs，即MMP-1、MMP-2和MMP-9。尚未探讨另外的胶原酶MMP-8和MMP-13是否也被MMP-7激活。我们在此表明，重组活性MMP-7能够在体外将MMP-8加工成其活性形式，但不能激活MMP-13。在缺乏MMP-7基因的小鼠左心室中，体内MMP-8水平升高而MMP-13水平降低。MMP谱的这种变化并未伴随左心室尺寸或壁厚度的改变。总之，这些数据表明MMP-8是MMP-7的体内底物，并且在没有MMP-7的情况下前MMP-8的积累下调前MMP-13水平以维持基线胶原降解功能。MMP-8和MMP-13之间的相互作用表明这些MMPs可能发挥相互作用的作用。因此，选择性MMP抑制剂的设计必须考虑平行MMP类型的变化作为潜在的补偿机制。
