Matrix metalloproteinases (MMPs) are a well studied family of proteolytic enzymes. In the liver, as in other solid organs, MMPs play a key role in maintaining the integrity of the extracellular matrix. Excessive MMP activity has been demonstrated to occur in the liver in response to a variety of acute and chronic insults. This results in the loss of structural proteins that maintain the normal architecture of the liver and the recruitment and activation of inflammatory cells that perpetuate liver damage.
The expression pattern of MMPs within the liver is primarily restricted to several members of this large protease family. Key among these subtypes are MMP 2, MMP 9 and MMP 13, each of which has been implicated in the progression of liver damage. The principle sources of MMP activity in the liver is derived from activated stellate and activated Kupffer cells. This is shown in Figure 2, along with an abbreviated list of their activities. Each of these MMPs is known to be significantly upregulated in disease models as well as in human liver disease.
Studies in disease models in which individual MMPs have been genetically deleted highlight their significance in the pathways leading to liver damage. In addition, studies with small molecule inhibitors have also demonstrated efficacy in a variety of models of liver damage.
MMPs are attractive mechanism to target in the setting of liver disease. First, these enzymes are directly involved in the acute and chronic inflammatory pathways involved in liver damage. Second, these enzymes are especially highly expressed in a variety of liver diseases. Third, in addition to the role in inflammation these enzymes are also involved in maintaining the structural integrity of the liver and progression of fibrogenesis. And lastly, the mechanism offers the potential to be additive or synergistic with other mechanisms of hepatoprotection currently under development.
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