Special articleExpression of MMPs and TIMPs in liver fibrosis – a systematic review with special emphasis on anti-fibrotic strategies
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)
Tissue inhibitors of metalloproteinases in liver fibrosis
Int J Biochem Cell Biol
(1997)- et al.
Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis
Hepatology
(1996) - et al.
Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1
J Hepatol
(1999) - et al.
Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride
J Hepatol
(2000) - et al.
Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen
J Biol Chem
(2004) - et al.
Cellular activation of proMMP-13 by MT1-MMP depends on the C-terminal domain of MMP-13
FEBS Lett
(2002) - et al.
Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta
J Biol Chem
(1989) - et al.
Reciprocal modulation of matrix metalloproteinase-13 and type I collagen genes in rat hepatic stellate cells
Am J Pathol
(2003) - et al.
Expression of matrix metalloproteinase-13 and tissue inhibitor of metalloproteinase-1 in acute liver injury
J Hepatol
(1999) - et al.
Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors
Gastroenterology
(2003)