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PubMed1997

Differential distribution of five members of the matrix metalloproteinase family and one inhibitor (TIMP-1) in human liver and skin.

Matrix metalloproteinases represent a family of zinc-dependent proteolytic enzymes thought to be involved in normal and disease-related tissue remodeling processes. Increasing information about these enzymes is becoming available concerning their primary sequences, regulation at the mRNA level, activation of proenzymes, and modulation of enzyme activity by tissue inhibitors. In contrast, their morphological distribution and biological functions in normal tissues are poorly understood. In the present report, the comparative distribution of five members (gelatinase-A, gelatinase-B, matrilysin, stromelysin-1, and stromelysin-3) of the matrix metalloproteinase family and of one inhibitor (TIMP-1) has been morphologically analyzed in human liver and skin with the aid of new monospecific antibodies. Because of their common designation as matrix proteinases, these enzymes might have been expected to be distributed throughout these tissues, or at least in the connective tissue. However, each member of the family produces a highly specific pattern, staining structures such as arteriolar smooth muscle cells, myoepithelial cells in secretory portions or the luminal lining in excretory ducts of dermal sweat glands, liver bile canaliculi, or structures surrounding peripheral nerve axons. No reactivity is detected in rat tissues.

Animals↗

PubMed2005

Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome.

Matrix metalloproteinases (MMPs) play an important regulatory role in many biological and pathological processes and their specific role in Alport syndrome (AS) is not yet clearly defined. In this study, the naturally occurring canine X-linked AS was used to demonstrate a potential role for MMP-3 and MMP-7 in Alport renal pathogenesis. Recently, we demonstrated that the expression of MMP-2, MMP-9 and MMP-14 was upregulated in the renal cortex of dogs with a spontaneous form of XLAS. In the present study, we examined necropsy samples of renal cortex from normal and XLAS dogs for MMP-3 and MMP-7 as they have the potential to activate MMP-2 and MMP-9. Immunohistochemical analysis showed strong immunostaining for both MMP-3 and MMP-7 in the interstitial space of XLAS kidneys, while virtually no immunostaining was observed in similar fields from normal dogs. RT-PCR and casein zymography confirmed that both mRNA transcripts and activities of MMP-3 and MMP-7 are elevated in XLAS kidneys. The induction of these MMPs likely contributes to tissue destruction associated with the fibrogenic process, while augmenting the activation of MMP-2 and MMP-9 by MMP-3 and MMP-7 in XLAS. Thus, these data further implicate a role for the MMPs in progressive renal pathogenesis associated with AS.

Animals↗

PubMed2003

The expression of matrix metalloproteinase matrilysin indicates the degree of inflammation in ulcerative colitis.

BACKGROUND: Any alteration in the synthesis and breakdown of the extracellular matrix is important in tissue remodeling during inflammation and wound healing. The degradation of the extracellular matrix components is regulated by a cascade of matrix metalloproteinases (MMPs). The present study attempted to assess the relationship between MMPs and the degree of inflammation in ulcerative colitis. METHODS: The expression of MMPs, including MMP-1, -2, -3, -7 (matrilysin), and -9, and that of their inhibitors (tissue inhibitor of metalloproteinases [TIMP]-1 and -2) were analyzed immunohistochemically by using 52 formalin-fixed and paraffin-embedded specimens from patients with ulcerative colitis who had undergone a biopsy or surgery. RESULTS: It was observed that MMP-1, -2, and -9, and the TIMPs were expressed in stromal cells, MMP-3 was expressed in both the epithelial cells and stromal components, and matrilysin was expressed only in the epithelial cells on the edge of ulcers. The expression of the MMPs was increased compared with that of the TIMPs. The frequency of matrilysin expression was increased corresponding to the severity of the inflammation. Matrilysin was also expressed in epithelial cells with dysplasia and cancer. CONCLUSIONS: Matrilysin expression could be an important marker of activity and could be used for the prediction of subsequent transformation in patients with ulcerative colitis.

Adolescent↗

PubMed1996

Matrilysin is associated with progression of colorectal tumor.

Matrilysin and gelatinase A, B mRNA expressions were examined in colorectal tumors. Matrilysin mRNA was observed exclusively in tumors, while the others were also found in normal mucosa surrounding tumors. Further analysis revealed that colorectal adenomas with severe dysplasia, not with mild dysplasia, expressed matrilysin with lower levels than cancers. The level of matrilysin mRNA expression increased with the advancement of stages of colorectal cancers, consequently a relatively higher expression was observed in liver metastatic tumors than primary tumors. These results suggest that matrilysin mRNA expression was correlated with the progression of colorectal tumors, and this enzyme may also play a role in developing metastatic tumors in liver.

Adenoma↗

PubMed2005

EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells.

The IGF/IGF-1R system, which includes the IGF, IGF-1R, and IGFBPs proteins, plays an important role in the development and growth of colorectal cancer. We previously reported that in the HT29 human colon cancer cell line EGCG, the major biologically active component of green tea, inhibits activation of the RTKs EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways. Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer cells. We found that the colon cancer cell lines Caco2, HT29, SW837, and SW480 express high levels of the IGF-1R receptor, and that both SW837 and SW480 cells display constitutive activation of this receptor. Treatment of SW837 cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused within 6 h a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein. At 12 h, there was a decrease in the levels of both IGF-1 protein and mRNA and within 3-6 h there was an increase in the levels of both IGFBP-3 protein and mRNA. The increased expression of the latter protein was sustained for at least 48 h. When SW837 cells were treated with EGCG for a longer time, i.e., 96 h, a very low concentration (1.0 microg/ml) of EGCG also caused inhibition of activation of IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNAs that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-beta2, an inducer of IGFBP-3 expression. These findings expand the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation, providing further evidence that EGCG and related compounds may be useful in the chemoprevention or treatment of colorectal cancer.

Catechin↗

PubMed2005

Apolipoprotein C-II is a novel substrate for matrix metalloproteinases.

We previously reported an efficient proteomic approach to identify matrix metalloproteinase (MMP) substrates from complex protein mixture. Using the proteomic approach, apolipoprotein C-II (apoC-II), which is a cofactor of lipoprotein lipase (LPL) and a component of very-low density lipoprotein and chylomicron, has been identified as a putative MMP-14 substrate. Cleavage of apoC-II, with various MMPs, demonstrated that apoC-II is cleaved most efficiently by MMP-14, and also by MMP-7, among the tested MMPs. The 79-amino acid residue apoC-II was cleaved between Asn35 and Leu36 by MMP-14, and between Phe14 and Leu15 and between Asn35 and Leu36 by MMP-7. Cleavage of apoC-II by MMP-14 markedly decreased LPL activity and would thus impair hydrolysis of triglycerides in plasma and transfer of fatty acids to tissues. Our result suggests that cleavage of apoC-II by MMPs would be important for development of pathophysiological situations of apoC-II deficiency such as atherosclerosis.

Amino Acid Sequence↗

PubMed2006

Proteolytic processing by matrix metalloproteinases and phosphorylation by protein kinase CK2 of fetuin-A, the major globulin of fetal calf serum.

Bovine fetuin-A is a member of a glycoprotein family with a wide spectrum of functions. Until now the bovine protein has been thought to be a single-chain protein. Recently we have shown that native bovine plasma fetuin-A partially exists as a disulfide-bridged two-chain protein with a heavy N-terminal and a lighter C-terminal chain similar to the structure of human fetuin-A homologue (alpha2HS glycoprotein), and also is partially phosphorylated at residues Ser120, Ser302, Ser305 and Ser306 (Wind et al., Anal. Biochem. 317 (2003) 26-33). Both fetuin-A modifications, the phosphorylation at the four sites as well as the proteolysis which causes longer or shorter light chains (termed lc-1 and lc-2, respectively), are probably brought about by targeted enzymatic activities which still need to be defined. In this study we show that authentic bovine fetuin-A disulfide-bridged two-chain forms, which include the original C-terminus, were liberated from the single-chain precursor by metalloproteinases MMP-3 (stromelysin-1) and MMP-7 (matrilysin), but not by elastase, cathepsin E and cathepsin G. Peptide sequencing suggested cleavage sites chiefly at the Pro277-Ser278 or Arg294-His295 peptide bonds. Fetuin-A radioactive phosphorylation in vitro by protein kinase CK2 caused (32)P incorporation into the fetuin-A light chain lc-1 but not lc-2 or the fetuin-A heavy chain, as revealed by MMP assisted proteolysis. Analysis by nanoESI-MS pinpointed phosphorylation at the native phospho-residues Ser302, Ser305 and Ser306 by increased relative abundance following in vitro phosphorylation. Moreover, CK2 phosphorylation of synthetic C-terminal fetuin-A peptides, used as effective controls to the native protein, strongly implies that CK2 is involved in the in vivo phosphorylation of fetuin-A. The phosphorylation of N-terminally truncated peptide homologs seemed highly dependent on the sequence context N-terminal of the phosphorylation sites, thus providing a likely explanation for the non-phosphorylation of the light chain lc-2 in native fetuin-A.

Amino Acid Sequence↗

PubMed2005

Matrilysin over-expression in MCF-7 cells enhances cellular invasiveness and pro-gelatinase activation.

Matrilysin (MMP-7) is over-expressed in various cancers and is thought to play important roles in tumor invasion and metastasis. However, the function of MMP-7 in breast cancer remains unclear. We therefore examined the expression of the MMP-7 gene in breast cancer (MCF-7) cells and the effect of its over-expression on cellular invasion. We transfected human MMP-7 into MCF-7 cells and selected clones that stably over-expressed the MMP-7 gene. The in vitro invasiveness of MCF-7 cells was quantified by use of the Matrigel invasion assay. Expression of MMP-7 mRNA was analyzed by quantitative RT-PCR. MMP secretion and activation were detected by gelatin zymography. We found that MMP-7-expressing clones had significantly increased invasion (P < 0.001), with increased MMP-7 expression and gelatinase activation as compared to the vector controls. We conclude that MMP-7 over-expression correlates with breast cancer in vitro invasiveness and that MMP-7 may promote invasion by increasing the secretion and activation of proMMP-2 and proMMP-9.

Breast Neoplasms↗

PubMedDate not supplied

Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation?

Matrilysin or MMP-7, one of the smallest of all known matrix metalloproteinases (MMPs), has been studied extensively in many different tumor types, since its discovery more than 20 years ago. However, research during the past several years has revealed that this protease also plays an essential role in innate immunity, and, more particularly, in inflammatory disorders.

Animals↗

PubMed2004

The relationship between plasma MMP-1, -7, -8 and -13 levels and embolic potential during carotid endoluminal intervention.

BACKGROUND: Patients undergoing carotid endoluminal intervention are at risk of embolic stroke even with the use of distal protection devices. Matrix metalloproteinases (MMPs) have been implicated as a causal factor in plaque instability leading to spontaneous embolisation. We investigated whether plasma MMP levels correlated with the embolisation during carotid endoluminal intervention. METHODS: Thirty circumferentially intact carotid endarterectomy specimens were subjected to a standardised angioplasty procedure in a pulsatile ex vivo model. Emboli collected in a series of distal filters were counted and sized. Plasma samples were collected pre-operatively and analysed for MMP-7 and MMP-8 levels using Western immunoblotting. MMP-1 and MMP-13 levels were determined using ELISA. Emboli number and maximum size were correlated with plasma levels of the MMPs using Spearmans rank. RESULTS: Total MMP-8 levels were related to maximum embolus size (r=0.442, p=0.005) but not emboli number (r=0.342, p=0.052). MMP-1, -7 and -13 were not correlated with either emboli number or with maximum embolus size. CONCLUSION: Pre-operative plasma MMP-8 levels are related to the size of emboli from plaques during carotid endovascular intervention. Further in vivo studies need to be performed to assess the importance of this finding. There is potential for development of plasma markers to identify those patients at greater risk of embolic stroke during carotid endoluminal intervention.

Aged↗

PubMed2005

Expression of matrix metalloprotease-2, -7 and -9 on human colon, liver and bile duct cell lines by enteric and gastric Helicobacter species.

Gastric and enteric Helicobacter species have been associated with malignant and inflammatory diseases of the stomach, liver, gall bladder and intestine. Matrix metalloproteinases (MMPs) participate in degradation of extracellular matrix, which allows bacteria to come in contact with and interact with the cells. Enhanced level of MMPs facilitates metastasis and cell invasion of tumor cells by removal of physical barriers, as well as modulation of biologic activities of the proteins residing in the extracellular matrix. The aim of this study was to evaluate the effect of gastric and enteric Helicobacter on induction of MMPs in hepatocytes and epithelial cells of gall bladder and colon. Human hepatocytes HepG2, gall bladder epithelial cells TFK-1, and colon epithelial cells HT29 were infected with strains of H. pylori cagA+, cagE+, H. pylori cagA-, cagE-, H. pullorum, H. cholecystus, H. bilis and H. hepaticus. Protein levels of MMPs were analyzed by enzyme-linked immunosorbent assay and immunohistochemistry. Reverse transcription-quantitative polymerase chain reaction was used to study mRNA levels. Increased expression of MMP-2 and MMP-9 was observed on HepG2, TFK-1 and HT29 infected with H. pylori cagA+, cagE+ and H. cholecystus strains. H. pylori cagA+, cagE+, H. cholecystus, H. pullorum, H. bilis and H. hepaticus strains increased expression of MMP-7 on HT29, compared to uninfected control cells. The effect of MMP upregulation on HepG2, TFK-1 and HT29 was bacterial dose dependent. H. pylori cagA-, cagE- strain did not increase expression of MMPs. Inducible MMPs on colon and bile duct epithelial cells as well as hepatocytes may play an important role in facilitating invasion and progression of cancer by Helicobacter species colonizing the hepatobiliary and gastrointestinal tract.

Bile Ducts↗

PubMed2005

Filter sterilization of highly infectious samples to prevent false negative analysis of matrix metalloproteinase activity.

Matrix metalloproteinases (MMPs) are implicated in the immunopathology of numerous infectious diseases. High risk samples such as those generated after infection with Mycobacterium tuberculosis require filter sterilization for safe analysis of MMP concentrations. Here, we report that commercial filter membranes may cause artefacts by binding MMPs. Anopore 0.2 microM membrane filtration reduced MMP-1 concentrations to undetectable levels by zymography and Western blotting. Polypropylene 0.45 microM filtration removed some MMP-1, while Polysulphone, Durapore and Bio-inert 0.2 microM membranes did not remove MMP-1. Anopore filtration also removed all MMP-7 and -9 activity, suggesting that the conserved MMP catalytic domain binds the membrane. This study demonstrates the importance of selecting the appropriate filter in MMP analysis to avoid incorrectly excluding MMP involvement in infection-related immunopathology.

Binding Sites↗

PubMed2005

The Pathogenesis of floppy eyelid syndrome: involvement of matrix metalloproteinases in elastic fiber degradation.

OBJECTIVE: To investigate histopathologic alterations of eyelid biopsy specimens from patients with floppy eyelid syndrome (FES) with special regard to elastic fiber content and ultrastructure as well as to the expression of elastin-degrading enzymes to elucidate the pathogenesis of this disorder. DESIGN: Retrospective, interventional case series. PARTICIPANTS AND CONTROLS: Eleven consecutive patients with FES and 10 age-matched control patients with basal cell carcinoma of the eyelid. METHODS: Horizontal pentagonal eyelid resections of 16 upper lids were performed in 11 patients with FES. Full-thickness eyelid biopsy specimens from study and control patients were examined by light and transmission electron microscopy, semiquantitative morphometry, and immunohistochemistry using antibodies against matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MMP-12 and neutrophil elastase. RESULTS: All patients treated with surgical horizontal eyelid shortening were asymptomatic at follow-up. Histopathologic analysis of the surgical specimens showed, apart from unspecific signs of chronic inflammation, a significant decrease in the amount of elastin within the tarsal plate and eyelid skin as compared with controls. Residual elastic fibers revealed an abnormal ultrastructure with a diminished elastin core. Immunohistochemistry demonstrated an increased immunoreactivity for elastolytic proteases, particularly MMP-7 and MMP-9, in areas of elastin depletion in FES specimens as compared with controls. CONCLUSIONS: The findings indicate that upregulation of elastolytic enzymes, most probably induced by repeated mechanical stress, participates in elastic fiber degradation and subsequent tarsal laxity and eyelash ptosis in FES.

Aged↗

PubMed2004

Lysophosphatidic acid enhances epithelial ovarian carcinoma invasion through the increased expression of interleukin-8.

OBJECTIVE: We previously reported that lysophosphatidic acid (LPA) stimulates cellular invasion of ovarian cancer (OVCA) cells by enhancing membrane-type-1-matrix metalloproteinase (MT1-MMP)-mediated activation of MMP2. Here, we investigate a second mechanism in which LPA enhances cellular invasion through the increased expression of IL-8, independent of the expression or activation of MMP2. METHODS: Epithelial ovarian carcinoma cells (DOV 13) were exposed to LPA (80 microM) and IL-8 (100 ng/ml) for 24 h. IL-8 expression was quantified by enzyme-linked immunosorbent assay (ELISA). Cellular invasion (Matrigel invasion), migration (colloidal gold), and urinary-type plasminogen activator (uPA) activity (colorimetric assay) were quantified. Conditioned medium was also assayed for MMP activation and expression by SDS-PAGE gelatin zymography, ELISA, and Western blotting. In addition, IL-8 neutralizing antibody and MMP inhibitors were employed. RESULTS: Our results found LPA to increase IL-8 expression threefold. IL-8 did not affect cellular migration, MMP2 activation, or uPA expression. However, exposure to various concentrations of IL-8 increased cellular invasiveness. Using an IL-8 blocking antibody and various MMP inhibitors, we determined that the increase in invasion was IL-8-dependent, while independent of the activation of MMP2 or MMP9. We further determined IL-8 exposure increased the expression of matrilysin (MMP7). Cells exposed to LPA and IL-8 resulted in a synergistic effect on cellular invasion. Adding the IL-8 blocking antibody, slightly decreased cellular invasion, indicating LPA in part, increases cellular invasion through the increased expression of IL-8. CONCLUSION: We have identified a separate mechanism of enhanced cellular invasion, which is independent of MMP2 activation and involves the increased expression of IL-8 and subsequent increased expression of MMP7.

Cell Line, Tumor↗

PubMed2002

Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms.

Acquired abdominal aortic aneurysms are usually associated with a mural thrombus through which blood continues to flow. Some early data suggest that aneurysmal evolution correlates with the biological activity of the thrombus. Our hypothesis was therefore that the thrombus could adsorb blood components and store, release, and participate in the activation of proteases involved in aneurysmal evolution. For this purpose, we have explored both the metalloproteinase and fibrinolytic systems in the thrombus and the wall of human aneurysms. We have first investigated blood clot formation and lysis in vitro. Spontaneous clotting induces a release of promatrix metalloproteinase (pro-MMP)-9 into the serum that was fourfold higher than in paired control plasma (P < 0.001). Fibrinolysis progressively released more MMP-9 in a time-dependent manner (P < 0.01). After selective isolation, we demonstrated that polymorphonuclear leukocytes are the main source of MMP-9 release during clot formation. Protease content was then analyzed in 35 mural thrombi and walls of human abdominal aortic aneurysms sampled during surgical repair. In 15 aneurysms, the liquid phase at the interface between the thrombus and the wall was sampled separately. Both thrombus and wall contained MMP-2 and MMP-9 but the ratio MMP-9/MMP-2 was higher in the thrombus than in the wall. The liquid interface also contained active MMP-9. Immunohistochemistry of the thrombus confirmed these findings, showing the presence of polymorphonuclear leukocytes at the luminal pole of the thrombus, co-localizing with MMP-9 storage. In contrast, MMP-3 and MMP-7 were only present in the aneurysmal wall. Plasminogen was present in the mural thrombus but plasmin activity was present in both thrombus and wall. In the liquid interface, plasmin-alpha(2)-anti-plasmin complexes were detected demonstrating in vivo the activation of plasminogen. In contrast, u-PA and t-PA were detectable only in the wall, suggesting that plasminogen present in the thrombus could be activated by factors secreted by the arterial wall. This was demonstrated in vitro, in which co-incubation of thrombus and wall extracts generated plasmin in the presence of a fibrin matrix and activated MMPs. In conclusion, our study strongly suggests that the mural thrombus, by trapping polymorphonuclear leukocytes and adsorbing plasma components could act as a source of proteases in aneurysms that may play a critical role in enlargement and rupture.

Abdominal Wall↗

PubMed2000

Multiple sclerosis: pro- and anti-inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-beta.

Interferon-beta (IFN-beta) has a beneficial influence on the course of multiple sclerosis (MS) and has become standard treatment of this disease, though its mechanisms of action are incompletely understood. This study examines the effect of IFN-beta treatment on the cytokines IL-6, TNF-alpha, IFN-gamma and IL-10; the metalloproteinases MMP-3, -7 and -9 and the tissue inhibitor of metalloproteinase-1 (TIMP-1). IFN-beta treatment resulted in decreased numbers of mononuclear cells (MNC) secreting IL-6 and TNF-alpha and expressing mRNA of MMP-3 and MMP-9 compared to pretreatment levels. On the contrary, numbers of IL-10 secreting MNC and TIMP-1 mRNA expressing were augmented during IFN-beta therapy. Whether the down-regulatory effects on pro-inflammatory and upregulatory effects on anti-inflammatory molecules are a direct result of IFN-beta on the immune system or secondary to clinical stabilization of MS pathology induced by IFN-beta remains to be evaluated.

Cells, Cultured↗

PubMed1999

Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system.

The role of extracellular proteolysis in inflammatory demyelination, originally hypothesized as a mechanism for myelin degradation, is increasingly recognized as a pathogenetic step and as a target for therapy in human demyelinating disease. The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including multiple sclerosis (MS), is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs): collagenases, stromelysins, membrane-type metalloproteinases and gelatinases. Spatiotemporal protein and mRNA expression of gelatinase B (MMP-9) and matrilysin (MMP-7) have been documented respectively in MS lesions and in the central nervous system (CNS) of animals developing experimental autoimmune encephalomyelitis (EAE). A close interaction between disease-promoting cytokines and extracellularly acting proteases is deduced from in vitro experiments. Cytokines regulate the balance between the proteases and their respective specific inhibitors at the transcriptional level, while proteolysis is a reciprocal mechanism to enhance (by activation) or downmodulate (by degradation) the specific activities of cytokines. In acute inflammation the contribution of chemokines is hierarchically organised, interleukin-8 (IL-8) and related CXC-chemokines inducing a rapid influx of neutrophils in the acute lesions and an instantaneous exocytosis of gelatinase B granules. This results in sudden and extensive damage to the CNS. In chronic disease involving autoimmune processes CC-chemokines that act mainly on mononuclear cell types appear to be more strictly regulated. As MMPs modify matrix components, promoting extravasation of lymphocytes and monocytes/macrophages and have the potential to generate encephalitogenic peptides from myelin basic protein, novel treatments for demyelinating diseases may be predicted by specific inhibition of these enzymes. Here we review plasminogen activators and the MMP family, in the context of their role in CNS inflammation and demyelination and highlight studies in which intervention in these protease cascades are and may be used to treat demyelinating diseases.

Animals↗

PubMed2001

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.

BACKGROUND/AIMS: To study whether expression of matrix metalloproteinases and their inhibitors correlate with ongoing fibrogenesis, we measured hepatic mRNA levels of matrix metalloproteinase (MMP) -2, MMP-7, and MMP-9 as well as tissue inhibitor of metalloproteinase (TIMP) -1, TIMP-2, and TIMP-3 and compared it to histology, procollagen IV alpha-1 chain mRNA levels, and biochemical parameters in patients with chronic active hepatitis C (CAH). METHODS: Quantitative reverse transcription-polymerase chain reaction/enzyme-linked immunossorbent assay using in vitro transcribed competitor and standard RNA were performed from ten normal livers (N), 29 CAH liver biopsies and seven samples with hepatitis C virus (HCV)-induced end-stage cirrhosis (Ci). RESULTS: From N to Ci both TIMP and MMP RNA expression increased. However, none of the RNA levels differed significantly between CAH patients with and without fibrosis. Non-parametric correlation analysis and receiver operating characteristics curves show that MMP-2, MMP-7, and TIMP-1 provide the best discrimination between cirrhosis and pre-cirrhotic stages. They also correlate with histologic and biochemical inflammatory activity and with procollagen IV mRNA. CONCLUSION: Hepatic fibroproliferation is associated with alterations of hepatic TIMP and MMP expression. The relation of hepatic TIMP and MMP mRNA levels to disease stage and inflammatory activity underlines their potential as diagnostic markers in chronic liver disease.

Base Sequence↗