Extracellular matrix degradation and the role of hepatic stellate cells.

Following liver injury, hepatic stellate cells (HSCs) become activated and express a combination of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs). In the early phases of liver injury (and primary cell culture), HSCs transiently express MMP-3, MMP-13, and uroplasminogen activator (uPA) and exhibit a matrix-degrading phenotype. In the later stages of liver injury and HSC activation, the pattern changes and the cells express a combination of MMPs that have the ability to degrade normal liver matrix, while inhibiting degradation of the fibrillar collagens that accumulate in liver fibrosis. This pattern is characterized by the combination of pro-MMP-2 and membrane type 1 (MT1)-MMP expression, which drive pericellular generation of active MMP-2 and local degradation of normal liver matrix. In addition there is a marked increase in expression of TIMP-1 leading to a more global inhibition of degradation of fibrillar liver collagens by interstitial collagenases (MMP-1/MMP-13). These pathways play a significant role in the progression of liver fibrosis. Following cessation of liver injury, the pattern reverses and TIMP-1 in particular is rapidly downregulated. This phase is characterized by increasing activity of collagenases, degradation of liver matrix, and regression of liver fibrosis.