After tissue damage, or events such as organogenesis, pregnancy, wound healing or cancer, a well-regulated, highly complex regenerative process is initiated to reestablish the previous architecture and function of the damaged tissue. As part of this response, the extracellular matrix (ECM) must be rearranged, and multiple proteolytic enzymes are used to degrade the matrix prior to rebuilding. These proteolytic enzymes and their control mechanisms are known to be exploited by pathological processes, such as cancer dissemination, which ultimately lead to destruction and loss of function of the tissue architecture. If it were known exactly how matrix degradation takes place, it might be possible to develop novel therapeutics that specifically inhibit key players in pathological tissue remodeling processes.
The study shows that one of the ECM proteolytic enzymes, the matrix metalloproteinase MMP9, protects mice that are also deficient for the protease plasmin from developing lethal inflammatory mass lesions in the colon. The lethal lesions develop from microscopic colon lesions caused by the inability of mice lacking functional plasmin to break down fibrin. MMP9 is not expressed in healthy colon mucosa but is delivered to the microscopic lesions in the colons of plasmin-deficient mice by invading inflammatory cells. However, in contrast to the combined lethal effects of MMP9 and plasmin deficiency during colon tissue homeostasis, male mice deficient for both MMP9 and plasmin do not differ from plasmin single-deficient mice in terms of incisional skin wound healing, implying that, under certain circumstances, other proteases are able to substitute for MMP9.
Implications and future directions
This study contributes to a detailed understanding of the interplay between the various classes of extracellular proteases. Furthermore, if a functional overlap between different proteases that are active during pathological processes (e.g. cancer invasion) exists, potential therapies that specifically inhibit a single extracellular protease might be ineffective. A detailed understanding of each of the existing extracellular proteases, including their expression pattern during physiological and pathological events, and their preferred substrates, will provide an opportunity to combine drugs to inhibit extracellular proteases that can substitute for each other, thus obtaining the complete inhibition of the targeted process.
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