Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats

Abstract

Matrix metalloproteinase-II (MMP-II, 72-kd type IV collagenase, or gelatinase) is one of the gene families of zinc enzymes capable of degrading extracellular matrix molecules, and specifically of degrading type IV and V collagens, gelatin, fibronectin, and elastin. In this study, we used both the liver fibrosis model and the reversibility model of experimental cirrhosis to clarify how MMP-II participates in liver fibrosis of rats. To produce fibrosis model, rats received subcutaneous injections of CCl4 twice weekly for 7, 9, or 14 weeks. For the reversibility model, rats were treated with CCl4 three times a week for 8 weeks and killed at 3, 7, 14, 28, or 42 days after discontinuation of treatment. MMP-II gene expression was studied by Northern hybridization technique, and gelatinase activity of MMP-II was examined by zymography using gelatin substrate. At the same time, an immunohistochemical study using anti-type IV collagen antibody was carried out. In liver fibrosis model, nodule formation was established at 14 weeks. Immunodeposit of type IV collagen was increased in wide fibrous septa and was clearly observed along sinusoidal wall. Gene expression of MMP-II increased up to 7 to 12 times compared with that of controls, with the expression rate being maximum at an intermediate stage of fibrosis. Zymography showed the expressions of both 65-kd latent MMP-II, which is confirmed to be activated by adding p-aminophenylmercuric acetate, and 62-kd active MMP-II during fibrosis. The expression of both forms increased 13 to 28 times as the fibrosis progressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma

“…Significant increases of MMP-2, MMP-9, TIMP-1 and TIMP-2 have been observed in an experimental hepatic fibrosis model. 20,38,39 The difference in E-cadherin expression between cirrhotic liver and noncirrhotic normal liver has not been observed in previous studies. 40 Our study demonstrated a significantly lower E-cadherin expression and higher expression of MMP-1, -7 in cirrhotic liver tissue in comparison to noncirrhotic liver tissue.…”

MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells

“…Deposition of all these ECM components occurs in fibrogenesis; HSC are major producers of ECM components and also express increased amounts of MMP2 that is activated in fibrotic livers. 28 Interestingly, collagen VI is a microfibrillar collagen that serves as a flexible anchor connecting collagen I and/or III fibers to each other. Collagen VI is abundant in both normal and fibrotic livers and surrounds the bundles of collagen fibers formed of collagens I and III fibrils.…”

Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions

“…This is in keeping with the results observed in experimental hepatic fibrosis in rats. 20 Regulation of MMP-2 processing has been poorly investigated in the context of liver fibrosis. The finding that myofibroblastic HSC cultured on plastic produce high levels of pro-MMP-2 but almost no active enzyme suggests that either cell-cell or cell-matrix interactions are involved in the processing of MMP-2.…”

“…A number of studies have emphasized the profibrogenic functions of MMP-2 during the early phase of hepatic fibrogenesis. 3,20,21,51 It was suggested that MMP-2 might promote myofibroblastic transdifferentiation of quiescent HSC through remodeling of the normal subendothelial matrix. 3 However, the mechanisms leading to MMP-2 activation in the fibrotic liver have not been clearly delineated.…”