Gene Expression of Matrix Metalloproteinases in Acute and Chronic Liver Injuries

18. Matrix metalloproteinases (MMPs) specifically degrade extracellular matrix (ECM) proteins and are involved in tissue remodeling during fibrotic and inflammatory processes. In addition, a number of studies have provided evidence for the involvement of MMPs and their inhibitors in various processes, including ovulation, embryogenic growth and differentiation, or tumor invasion and metastasis. Many different enzymes are involved in degrading the ECM of the liver. Molecular biological progress has shown that several metalloproteinases in the liver share certain characteristics, such as some degree of sequence homology, a catalytic mechanism that depends on zinc, activation of the secreted zymogen form by proteolytic cleavage, and inhibition of the activated form by tissue inhibitors of metalloproteinases (TIMPs). The activity of MMPs may be regulated at the level of gene transcription, during proenzyme activation, or during binding of the proenzyme or active enzyme to specific inhibitors. During liver fibrosis, the relative ratio of MMPs to TIMPs is decreased. Thus, fibrosis may be progressive because of a decrease in matrix degradation. Because chronic liver injury is caused by repeated tissue injury events, it is possible that the transforming growth factor (TGF)-β-driven induction of MMP-2 and TIMPs dominates the tissue repair reaction, which lacks an appropriate TNF-mediated induction of MMP, as observed in the early phase of the single CCl₄ injury model. Activated stellate cells in fibrotic liver show a low expression of MMPs and a high expression of TIMPs and respond to TGF-β1 with further upregulation of TIMP, reflecting the MMP/TIMP expression pattern detected in fibrotic livers.