Role of Matrix Metalloproteinase-2 in Liver Fibrosis

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DESCRIPTION (provided by applicant): Regardless of the etiology of chronic liver injury, the final common pathway for liver injury and failure is fibrosis. Fibrosis with subsequent complications of portal hypertension results in the death of patients awaiting liver transplantation. Given the severe shortage of donor organs, there is an urgent need to understand the molecular basis of hepatic fibrosis in order to develop effective anti-fibrotic strategies. Liver fibrosis is characterized by activation of hepatic stellate cells which orchestrate a shift in the normal extracellular (ECM) comprised of mostly collagen type IV to a high-density interstitial matrix composed of predominantly type I collagen. Therefore, potential antifibrotic strategies include reduction in type I collagen synthesis, stimulation of matrix degradation, and/or promotion of stellate cell apoptosis. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, produced by activated hepatic stellate cells (HSCs), is increased in patients with chronic hepatitis and cirrhosis, suggesting a causative role in the fibrotic process. MMP-2 is also capable of acting as a type I collagenase, is upregulated in both animal and human hepatic fibrosis, is increased during resolution of fibrosis, and is associated with stellate cell apoptosis, we hypothesize that MMP-2 may play a protective rather than deleterious role in chronic liver injury. MMP-2 -/- mice offer an opportunity to clarify the physiologic role of MMP-2 in liver fibrosis. This study will employ the use of CCI4-induced chronic liver injury model to determine whether MMP-2 is important in attenuating liver fibrosis by directly reducing collagen I expression. Its role in acting as an interstitial collagenase will be assessed by 1) comparing the rate of spontaneous resolution of fibrosis between MMP-2 -/- and MMP-2 +/+ mice and 2) quantifying interstitial collagenase activity in both cohorts. In addition, a potential role for MMP-2 in promoting stellate cell apoptosis will be examined in both in vivo and in vitro models. Findings from these investigations may lead to novel approaches to the treatment of chronic fibrosing liver disease.