Inhibition of hepatic fibrogenesis by matrix metalloproteinase‐9 mutants in mice

Roderfeld, M; Weiskirchen, Ralf; Wagner, Sandra; Berres, Marie‐Luise; Henkel, Corinna; Grötzinger, Joachim; Gressner, A. M.; Matern, Siegfried; Roeb, Elke

doi:10.1096/fj.05-4828com

Cited by 124 publications

(121 citation statements)

References 61 publications

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“…180 Conversely, the use of MMP-9 mutant proteins as TIMP-1 scavengers reduces fibrosis accumulation by enhancing matrix resorption. 181 Stellate cells express uroplasminogen activator receptor and its inhibitor, as well as other components of the plasmin system. [182][183][184] Collectively, these findings suggest that stellate cells contain most, if not all, of the molecules necessary to either activate or inhibit metalloproteinases.…”

Section: Matrix Degradation and Resolution Of Fibrosismentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Matrix Degradation and Resolution Of Fibrosismentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…Another yet preclinical strategy is to block TIMP-1, a major effector of liver fibrosis, by use of a recombinant mutant protein derived from its high-affinity ligand MMP-9. 48 An intriguing novel target is the integrin ␣v␤6, a cell surface receptor that is expressed on activated epithelia during embryogenesis, wound healing, and tumorigenesis. 49 ␣v␤6 anchors these epithelia to a provisional ECM of tenascin and fibronectin 17 and through tethering latent TGF␤1 promotes its proteolytic activation.…”

Section: Antifibrotic Drug Developmentmentioning

confidence: 99%

Targeting Liver Fibrosis

2009

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We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (HEPATOLOGY 2009;50:1294-1306

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“…40,41 Furthermore, the mutation of MMP-9 was reported to inhibit hepatic fibrogenesis in mice. 42 This study showed that MMP-9 and TNF-a mRNA expression increased significantly with the activation of Kupffer cells that were positive for CD68 in group M, whereas switching the diet from MCDD to CD triggered the immediate recovery of MMP-9, suggesting that MMP-9 is associated with the activation status of Kupffer cells.…”

Section: Discussionmentioning

confidence: 60%

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

Ogawa

Kawada

2010

Laboratory Investigation

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Fatty liver disease has become a health problem related to metabolic syndrome worldwide, although its molecular pathogenesis requires further study. It is also unclear whether advanced fibrosis of steatohepatitis will regress when diet is controlled. The aim of this study was to investigate whether the resolution of fibrosis occurs in steatohepatitis induced by a methionine-choline-deficient diet (MCDD). Manifestation of endoplasmic reticulum (ER) stress in this model was also studied. Nonalcoholic steatohepatitis with advanced fibrosis was induced in rats by feeding them an MCDD for 10 weeks. Instead of MCDD, a methionine-choline control diet (CD) was given for the last 2 weeks to the experimental group. Fibrosis and inflammation were determined by tissue staining. Protein and gene expressions were determined by immunoblotting and quantitative reverse transcription-PCR (RT-PCR), respectively. Expressions of caspase-7, caspase-12, glucose-regulated protein 78 (GRP78), and protein disulfide isomerase were evaluated to clarify the presence of ER stress. Changing the diet from MCDD to CD triggered the reduction of fat in hepatocytes, a decrease in inflammatory gene expression and oxidative stress, and regression of fibrosis accompanied by the disappearance of activated stellate cells and macrophages. Immunohistochemistry, immunoblotting, and RT-PCR analysis all indicated the occurrence of ER stress in steatohepatitis, while it recovered immediately after changing the diet from MCCD to CD. The ratio of hepatocyte proliferation/apoptotis increased significantly during the recovery stage. This simple experiment clearly shows that changing the diet from MCDD to a normal diet (CD) triggers the resolution of hepatic inflammatory and fibrotic reactions and hepatocyte apoptosis, suggesting that MCDD-induced steatohepatitis is also reversible. ER stress appears and disappears in association with the generation and regression of steatohepatitis, respectively, with fibrosis.

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Inhibition of hepatic fibrogenesis by matrix metalloproteinase‐9 mutants in mice

Cited by 124 publications

References 61 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Targeting Liver Fibrosis

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

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