Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients

Abstract

BACKGROUND Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC). METHODS A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest ® and/or FibroScan ® . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays. RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 ( P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 ( P < 0.001). CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.

The Extra Virgin Olive Oil Polyphenol Oleocanthal Exerts Antifibrotic Effects in the Liver

“…Thus, we evaluated OC ability in affecting MMP mRNA expression in LX2 cells, observing that MMP2, 3 and 7 were significantly reduced by OC treatment, whereas only a decreasing tendency could be observed for MMP9, probably due to the high variability observed in the experiments. These results are in line with experimental and clinical observations, demonstrating the intriguing interplay between MMPs and collagen deposition, and reporting increased hepatic and plasmatic concentrations of some MMPs (in particular, MMP2, 7 and 9) in liver fibrosis ( 36 , 37 ).…”

Enzymes of Fibrosis in Chronic Liver Disease

“…A recent study reported that serum concentrations of MMPs are increased in chronic HCV infection, but gelatinases are inactive during fibrosis progression. When the collagenolytic activity was evaluated, lower values were found in METAVIR stages F2, F3, and F4 compared to stage F1 [ 96 ].…”

Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis

“…The mRNA and protein expression of several MMPs is modified during chronic hepatitis C: the gelatinases MMP-2 and -9 are enhanced [ 57 , 58 , 76 ], while the collagenases MMP-1 and -13 are downregulated [ 57 ]. A recent study reported increased serum levels of MMP-2, -7, and -9 in patients with chronic hepatitis C, which correlated to the fibrosis stage for MMP-7 [ 90 ]. Gelatinases contribute to the degradation of the basement membrane collagen IV, while collagenases such as MMP-1 and -13 break down interstitial collagens I and III.…”