The role of matrix metalloproteinase-13 in the regression of liver fibrosis

Abstract

The specific aims of this study were i) to determine the relative expression of MMP-13 in the regression of experimental live fibrosis; ii) to determine the cellular source of MMP-13 in resolving liver fibrosis; iii) to determine, mechanistically, the importance of MMP-13 in mediating regression of liver fibrosis.

Rats were treated for 4 or 12 weeks with carbon tetrachloride (CCI₄) to induce a reversible hepatic fibrosis or incompetently reversible cirrhosis respectively.

This study demonstrated that MMP-13 was expressed in progressive liver fibrosis and upregulated early during spontaneous recovery.  There was a correlation between MMP-13 expression and the presence of scar associated macrophages (SAMs).  Comparison between the 4 and 12 week rat CCI₄ models provided strong circumstantial evidence that SAMs were required for complete histological resolution. Indeed, peak expression of mmp13 mRNA after 12 weeks CCl₄ occurred at a time when the number of scar myofibroblasts was reduced, but macrophages were abundant and associated with scars.  LCM demonstrated that mmp13 mRNA was restricted to regions of fibrosis rich in SAMs.  Both MMP-13 mRNA and protein co-localised to large phagocytes within and apposed to hepatic scars.  Additionally, IHC in human cirrhotic tissue demonstrated MMP-13 may also play a role in remodelling of human liver fibrosis.  Using CD11b-DTR transgenic mouse to deplete SAMs early during resolution of CCI₄ fibrosis, SAM depletion resulted in a 5-fold reduction in mmp13mRNA (p=0.005) and persistence of hepatic scaring. One component of the mature hepatic scarring that persisted in the macrophage ablation model was elastin.  MMP-12 is the major hepatic elastase and a pilot model of CCI₄ fibrosis and recovery in MMP-12 deficient mice was undertaken.

In conclusion, these data indicate that SAMs selectively, during resolution of fibrosis, induce and utilise the major collagenase of MMP-13 to mediate the resorption of interstitial matrix and successfully remodel the fibrotic liver.

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