Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases

Abstract

Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.

Obeticholic acid reduces biliary and hepatic matrix metalloproteinases activity in rat hepatic ischemia/reperfusion injury

“…Extensive evidence supports a role for non-parenchymal cells, cholangiocytes, sinusoidal endothelial cell (SECs), hepatic stellate cells (HSCs), Kupffer cells (KCs) and other immune cells, including lymphocytes, in the production of MMPs and their specific inhibitors TIMPs [ 46 ]. Several studies have shown that MMP2, one of the most studied enzymes in liver fibrosis, is mainly secreted by KCs and by HSCs while MMP-9 (gelatinase B) is predominantly expressed in KCs but can be also expressed by neutrophils, macrophages and fibroblasts [ 43 ].…”

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

“…Hepatic fibrosis occurs when healthy liver tissues becomes scarred from chronic liver injury and inflammatory responses, and therefore cannot function normally [ 19 , 20 ]. Chronic liver damage leads to liver fibrosis in conjunction with the accumulation of ECM proteins, which is a typical characteristic of most chronic liver diseases [ 21 ]. Activated HSCs are major ECM-producing cells in an injured liver; these cells are activated by fibrogenic mediators, such as TGF-β [ 22 ].…”

Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products

“…Real-Time RT-PCR It was performed as previously described, 28) and the primers used were as follows: α-smooth muscle actin (α-SMA), 5′-ACT GGG ACG ACA TGG AAA AG-3′ and 5′-TAG ATG GGG ACA TTG TGG GT-3′; PDGF-Rβ, 5′-ATG CCT TAC CAC ATC CGC TC-3′ and 5′-ACA TTG CAG GTG TAG GTC CCC-3′; PDGF-B, 5′-AGG AGA CCC TTG GAG CCT AG-3′ and 5′-CAT CGA GAC AGA CGG ACG AG-3′; collagen type I alpha 2 (COL1A2), 5′-ACC TGG TCA AAC TGG TCC TG-3′ and 5′-GTG TCC CCT AAT GCC TTT GA-3′; and β-actin, 5′-TCC ACC TCC AGC AGA TGT GG-3′ and 5′-GCA TTT GCG GTG GAC GAT-3′.…”