Extracellular Matrix Metabolism and Fibrotic Disease

Abstract

Fibrosis and its end-stage cirrhosis are the result of chronic inflammatory liver disease. Historically considered irreversible, fibrosis has recently been demonstrated to be reversible. In this respect, the liver is a germane model to review extracellular matrix (ECM) remodelling and the fibrotic process. Upon injury hepatic stellate cells (HSCs) become activated and produce ECM components, including fibrillar collagens. The balance between ECM deposition and ECM degradation is skewed towards deposition by an increase expression of Tissue Inhibitors of Matrix metalloproteinases (TIMPs) versus Matrix Metalloproteinases (MMPs). In experimental models of spontaneous fibrosis resolution, liver TIMP levels decrease associated with HSC apoptosis or phenotypic reversion to quiescence; macrophages play a pivotal role in fibrolytic activity by increasing the expression of MMPs, thereby facilitating ECM degradation. Further investigations on the control of ECM deposition and degradation will likely facilitate the design of effective therapies aiming at resolving fibrosis by enhancing ECM degradation.