Special article
Expression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies

https://doi.org/10.1016/j.jhep.2007.02.003Get rights and content

In liver tissue matrix metalloproteinases (MMPs) and their specific inhibitors (tissue inhibitors of metalloproteinases, TIMPs) play a pivotal role in both, fibrogenesis and fibrolysis. The current knowledge of the pathophysiology of liver fibrogenesis with special emphasis on MMPs and TIMPs is presented. A systematic literature search was conducted. All experimental models of liver fibrosis that evaluated a defined anti-fibrotic intervention in vivo or in vitro considering MMPs and TIMPs were selected. The methodological quality of all these publications has been critically appraised using an objective scoring system and the content has been summarized in a table.

Section snippets

Background

The purpose of this review was threefold: first, to present the current knowledge of the pathophysiology of hepatic fibrogenesis and fibrolysis with special emphasis on matrix metalloproteinases (MMP) and their specific inhibitors (tissue inhibitors of metalloproteinases, TIMP); second, to provide a concise table aggregating all experimental approaches targeted towards inhibition of hepatic fibrogenesis or fibrolysis, respectively; and third, to critically evaluate the methodological quality of

MMPs and TIMPs in fibrogenesis

From the known MMPs only a few are expressed in liver tissue and differences between genotype and amino-acid sequence among species have to be considered. In rodents no human MMP-1 (collagenase-1) homologue is known. Nevertheless, sequential and functional similarity exists for rat and mouse MMP-13. MMP-13 is expressed by HSC [4], [5], fibroblasts, Kupffer cells, and perisinusoidal cells [6] and its synthesis can be upregulated by cytokines such as IL-1α, IL-1β, TNF-α or EGF [5], [7], [8], [9],

MMPs and TIMPs in fibrolysis

A principal feature of hepatic fibrosis is the disbalance between MMPs and TIMPs. Since either protein family is responsible for both, fibrogenesis and fibrolysis, renders them ideal targets for anti-fibrotic therapeutic interventions. Along these lines two strategies appear auspicious: upregulation of MMP activity or downregulation of TIMP activity.

Collagenases like MMP-1, -8, -13, and -14, possessing the ability to degrade fibrillar collagens, may well be responsible for key events in the

Recent experimental anti-fibrotic approaches

A number of interesting experimental studies regarding the role of MMPs and TIMPs in hepatic fibrosis have been conducted since the last reviews have been published [105], [106]. Moreover, since then, the methodological quality of both, clinical trials and basic research, has been challenged [107], [108], [109], [110], [111]. Therefore, in addition to a structured literature search and a table summarizing all relevant articles in the field, the methodological quality, and thus the strength of

Literature retrieval and study selection process

Medline was searched via the internet using the search engine PubMed© (http://www.ncbi.nih.gov/entrez/query.fcgi). Aim of the structured literature search was to identify all models of liver fibrosis that evaluated a defined anti-fibrotic intervention in vivo or in vitro considering MMPs and TIMPs. The primary search retrieved all studies published between January 2000 and June 2006 using the following search terms: “liver OR hepatic” (title & abstract) AND “metalloproteinase OR

Assessment of the methodological quality

Considering basic principles of good study methodology a checklist comprising four dichotomous variables was accomplished (Table 1). Although not formally validated, robust evidence exists that all individual items of the checklist are indeed associated with methodological quality [108], [110], [112]. Each item of the checklist scored one point, thus the maximum score was four points and the minimum score zero points. Based on the quality assessment articles scoring two points or less were

Results of the literature search and quality assessment process

The primary Medline search retrieved 243 potentially relevant articles, out of which 75 articles met the inclusion criteria and were finally eligible for this overview (Fig. 4 and Table 2). Out of this 44 articles (59%) scored two points or less, thus representing poor methodological quality only. Twenty-four articles scored three and seven articles were awarded four points. An explicit experimental question (null hypothesis) has been asked in 45 out of 75 publications (60%). Others just

Summary

The highly controlled interplay between MMPs and TIMPs is responsible for a constant turn-over of liver matrix and the maintenance of homeostasis and a healthy liver architecture. Acute liver injury may significantly disturb the susceptible equilibrium resulting in functional imbalance. In chronic liver injury, differently regulated MMP and TIMP expression leads to a positive feedback loop with subsequent fibrogenesis (an overview of the current knowledge with respect to expression profiles of

Acknowledgements

The authors are grateful to DeLano Scientific for using PyMOL as open-source software. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 542, TP C3 and RO 957/6-1) and the Kompetenznetzwerk Hepatitis (BMBF HepNet).

References (187)

  • A.Y. Strongin et al.

    Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease

    J Biol Chem

    (1995)
  • T. Takahara et al.

    Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers

    Hepatology

    (1997)
  • R. Lichtinghagen et al.

    Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C

    J Hepatol

    (2001)
  • T. Takahara et al.

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

    Hepatology

    (1995)
  • T. Watanabe et al.

    Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the rat

    J Hepatol

    (2001)
  • H. Will et al.

    The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation Regulation by TIMP-2 and TIMP-3.

    J Biol Chem

    (1996)
  • M.W. Harty et al.

    Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity

    Surgery

    (2005)
  • A.E. Kossakowska et al.

    Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis

    Am J Pathol

    (1998)
  • M. Parola et al.

    Oxidative stress-related molecules and liver fibrosis

    J Hepatol

    (2001)
  • K. Imai et al.

    Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties

    J Biol Chem

    (1995)
  • Y. Ogata et al.

    Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9

    J Biol Chem

    (1992)
  • V. Knauper et al.

    Biochemical characterization of human collagenase-3

    J Biol Chem

    (1996)
  • F.W. Shek et al.

    Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis

    Am J Pathol

    (2002)
  • Y. Murawaki et al.

    Serum matrix metalloproteinase-3 (stromelysin-1) concentration in patients with chronic liver disease

    J Hepatol

    (1999)
  • N. Ramos-DeSimone et al.

    Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion

    J Biol Chem

    (1999)
  • Q. Cao et al.

    Dilinoleoylphosphatidylcholine prevents transforming growth factor-beta1-mediated collagen accumulation in cultured rat hepatic stellate cells

    J Lab Clin Med

    (2002)
  • E. Roeb et al.

    TIMP-1 protein expression is stimulated by IL-1 beta and IL-6 in primary rat hepatocytes

    FEBS Lett

    (1994)
  • E. Roeb et al.

    Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2

    FEBS Lett

    (1995)
  • E. Roeb et al.

    TIMP expression in toxic and cholestatic liver injury in rat

    J Hepatol

    (1997)
  • J.P. Iredale

    Tissue inhibitors of metalloproteinases in liver fibrosis

    Int J Biochem Cell Biol

    (1997)
  • R.C. Benyon et al.

    Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver

    Gastroenterology

    (1996)
  • Y. Yata et al.

    Spatial distribution of tissue inhibitor of metalloproteinase-1 mRNA in chronic liver disease

    J Hepatol

    (1999)
  • H. Yoshiji et al.

    Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model

    Hepatology

    (2000)
  • H. Yoshiji et al.

    Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse

    Hepatology

    (2002)
  • F.R. Murphy et al.

    Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis

    J Biol Chem

    (2002)
  • Z. Wang et al.

    TIMP-2 is required for efficient activation of proMMP-2 in vivo

    J Biol Chem

    (2000)
  • E. Ueberham et al.

    Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis

    Hepatology

    (2003)
  • Y. Iimuro et al.

    Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat

    Gastroenterology

    (2003)
  • A.M. Preaux et al.

    Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2

    Hepatology

    (2002)
  • K. Holmbeck et al.

    MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover

    Cell

    (1999)
  • R.T. Aimes et al.

    Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments

    J Biol Chem

    (1995)
  • E.H. Kerkvliet et al.

    Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase

    Matrix Biol

    (1999)
  • E. Ohuchi et al.

    Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules

    J Biol Chem

    (1997)
  • S.S. Apte et al.

    The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis

    J Biol Chem

    (1997)
  • F. Siller-Lopez et al.

    Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis

    Gastroenterology

    (2004)
  • X. Zhou et al.

    Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells

    J Biol Chem

    (2004)
  • D. Schuppan et al.

    Matrix as a modulator of hepatic fibrogenesis

    Semin Liver Dis

    (2001)
  • R.P. Somerville et al.

    Matrix metalloproteinases: old dogs with new tricks

    Genome Biol

    (2003)
  • H.S. Lee et al.

    Differential role of p38 in IL-1alpha induction of MMP-9 and MMP-13 in an established liver myofibroblast cell line

    J Biomed Sci

    (2003)
  • H. Sakaki et al.

    Interleukin-1beta induces matrix metalloproteinase-1 expression in cultured human gingival fibroblasts: role of cyclooxygenase-2 and prostaglandin E2

    Oral Dis

    (2004)
  • Cited by (0)

    View full text