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PubMed1994

Cellular localization of matrix metalloproteinases in the abdominal aortic aneurysm wall.

PURPOSE: This study explores the source(s) of the matrix-degrading proteinases, matrix metalloproteinase 1 (MMP-1; interstitial collagenase), matrix metalloproteinase 3 (MMP-3; stromelysin 1), and matrix metalloproteinase 9 (MMP-9; gelatinase B), previously implicated in abdominal aortic aneurysm (AAA) development. The possible involvement of the plasmin cascade in the activation of these proteinases was also explored by examining the presence of the urokinase-type plasminogen activator (uPA) in aneurysm wall. METHODS: Immunohistochemical techniques were used to detect the presence of MMP-1, MMP-3 and MMP-9 proteins and uPA in fixed, paraffin-embedded tissue sections from AAA (n = 10) and control (n = 2) aortas. RESULTS: The MMP-9 protein was localized to mononuclear cells in the AAA wall. Dual-labeling techniques confirmed the identity of these cells as macrophages. The MMP-3 protein and uPA were also detected primarily in the macrophage-like mononuclear cells infiltrating the aneurysmal aorta. Immunoreactive material to MMP-1 was demonstrated in mesenchymal cells of the AAA wall suggesting alternative expression and delivery of this enzyme in AAA. CONCLUSIONS: This work establishes the role of macrophages in the delivery, expression, and possible activation of matrix destructive proteinases during AAA pathogenesis and suggests a role for the activation of MMPs in the progression of the disease.

Antibodies, Monoclonal↗
PubMed1999

Amniotic fluid matrix metalloproteinase-9 levels in women with preterm labor and suspected intra-amniotic infection.

OBJECTIVE: To determine the accuracy of amniotic fluid (AF) matrix metalloproteinase-9 measurements for diagnosing intra-amniotic infection in women with preterm labor. METHODS: We performed amniocenteses in 44 women between 22 and 35 weeks' gestation who presented to our center with preterm labor and clinical suspicion of intra-amniotic infection. Each sample was analyzed by glucose measurement, Gram stain, and culture for aerobes, anaerobes, and mycoplasmas. We tested the AF for matrix metalloproteinase-9 using gelatin zymography and a commercial enzyme-linked immunosorbent assay (ELISA) system. We calculated accuracy and confidence intervals (CIs) for AF matrix metalloproteinase-9, glucose, and Gram stain for diagnosing intra-amniotic infection, using culture as the criterion standard. RESULTS: All patients who had matrix metalloproteinase-9 detectable by ELISA also demonstrated matrix metalloproteinase-9 by zymography. Six cases of intra-amniotic infection were confirmed by culture (prevalence 14%). The performance statistics of AF matrix metalloproteinase-9 for diagnosing intra-amniotic infection were: sensitivity 83% (95% CI 53, 99), specificity 95% (95% CI 88, 99), positive predictive value 71% (95% CI 37, 99), and negative predictive value 97% (95% CI 92, 99). Two women had false-positive results; one had gram-negative rods on the AF Gram stain and developed clinical signs and symptoms of chorioamnionitis several hours after amniocentesis and the other had a purulent vaginal discharge and an AF glucose level less than 15 mg/dL. Both delivered within 24 hours of amniocentesis. CONCLUSION: Measuring matrix metalloproteinase-9 in the AF appeared to be reliable for diagnosing intra-amniotic infection. An elevated matrix metalloproteinase-9 concentration in the AF at a preterm gestational age may portend imminent delivery regardless of microbiologic confirmation of intra-amniotic infection.

Adult↗
PubMed2001

Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling.

Matrix metalloproteinases are thought to play an important role in endothelial cell migration and matrix remodeling. We have used an in vitro wound healing migration model and newly generated anti-membrane type 1-matrix metalloproteinase (MT1-MMP) monoclonal antibodies (mAbs) to characterize the role of MT1-MMP during this process. First, the expression and shedding of MT1-MMP are up-regulated upon induction of migration in endothelial cells, as demonstrated by flow cytometry and Western blot analysis. Furthermore, MT1-MMP is concentrated at discrete areas in migrating endothelial cells, in contrast to the diffuse pattern observed in confluent cells. Interestingly, migration of endothelial cells results in the stimulation of MT1-MMP activity, as shown by its ability to process pro-MMP-2 and to degrade fibrinogen assessed by zymography. Moreover, MT1-MMP-mediated gelatin degradation is enriched at migration sites. mAbs generated against the MT1-MMP catalytic domain are shown to inhibit MT1-MMP enzymatic activity and to impair both phorbol 12-myristate 13-acetate-induced endothelial migration and invasion of collagen and fibrin gels. Furthermore, a reduction in the formation of capillary tubes in Matrigel is also observed when endothelial cells are pretreated with the blocking anti-MT1-MMP mAbs. Altogether, these data demonstrate that MT1-MMP plays an important role during endothelial cell migration, and its activity can modulate endothelial migration, invasion, and formation of capillary tubes during the angiogenic response.

Antibodies, Monoclonal↗
PubMedDate not supplied

Correlation between interleukin-6 and matrix metalloproteinase-9 in early wound healing in children.

Interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid and their associations to cellular changes were determined in early wound healing. Wound healing of 75 children who underwent elective operations was studied with the Cellstick(R) device, which was inserted into the wound at the end of the operation and removed 3 or 24 hours post-wounding. Differential counts of the wound cells and interleukin-6 and matrix metalloproteinase-9 concentrations in the wound fluid were analyzed. Interleukin-6 and the matrix metalloproteinase-9 concentrations increased in parallel (r = 0.81). The proportion of wound neutrophils increased (p < 0.0001) and lymphocytes decreased (p < 0. 0001) between the observation times. The number of wound neutrophils had a strong correlation with both interleukin-6 (adjusted R2 = 0.41, p < 0.0001) and matrix metalloproteinase-9 concentrations (adjusted R2 = 0.37, p < 0.0001). The extracellular matrix degradation process of the early wound healing seems to be closely linked to the inflammatory response. Both of these measured markers are associated significantly with the neutrophil proportion in the wound.

Analysis of Variance↗
PubMed2002

Ets-1 upregulates matrix metalloproteinase-1 expression through extracellular matrix adhesion in vascular endothelial cells.

Ets-1 is a transcription factor regulating the expression of matrix-degrading proteinases and is believed to play a critical role in cell migration and tumor invasion. The aim of this study is to investigate the direct induction of ets-1 with consequential upregulation of collagenase-1 (MMP-1) by cell adhesion to extracellular matrix and to identify intracellular signal transduction pathways involved in ets-1 induction in cultured endothelial cells. The expressions of ets-1 mRNA and protein as well as MMP-1 protein were induced by cell adhesion to type I collagen and antisense ets-1 oligonucleotides impaired that MMP-1 expression. In addition, protein tyrosine kinase (PTK) and protein kinase C (PKC) inhibitors abrogated their induction, showing the suppression of focal adhesion kinase phosphorylation. These results suggest that ets-1 induced by cell adhesion to extracellular matrix directly upregulates MMP-1 expression via PTK and PKC activation in cultured endothelial cells.

Animals↗
PubMed2005

Physiological matrix metalloproteinase concentrations in serum during childhood and adolescence, using Luminex Multiplex technology.

Matrix metalloproteinases are a family of zinc-dependent proteinases which are involved in the breakdown and remodeling of extracellular matrix. As children grow and adolescents reach pubescence, their bodies undergo changes that require age-related morphogenesis of the extracellular matrix, possibly requiring unique patterns of matrix metalloproteinase (MMP) expression during periods of rapid tissue growth (i.e., childhood) or accelerated tissue remodeling and expansion (i.e., adolescence). Therefore, we have characterized age-specific and gender-specific differences in circulating concentrations of MMPs (specifically MMP-1, -2, -3, -8 and -9) in 189 serum samples obtained from healthy subjects, aged 2-18 years. MMP concentrations were measured using Fluorokine MultiAnalyte Profiling kits and a Luminex Bioanalyzer, as well as by commercial ELISA. Serum levels of MMP-1, -2, -3, -8, and -9 in healthy pediatric subjects represent log-normal distributions. MMP-2 was significantly negatively correlated with age (r=-0.29; p<0.001), while MMP-3 was significantly positively correlated with age (r=0.38; p<0.001). Although plasma, not serum, is considered the appropriate blood sample for measurement of MMP-8 and -9, serum levels of MMP-8 and -9 were also found to be highly positively correlated with each other (r=0.76; p<0.01). MMP results obtained by Fluorokin MultiAnalyte Profiling methods correlated well with conventional ELISA methods and use of this technology provided several advantages over ELISA.

Adolescent↗
PubMed2002

Keratinocyte stimulation of matrix metalloproteinase-1 production and proliferation in fibroblasts: regulation through mitogen-activated protein kinase signalling events.

Incubation of human dermal fibroblasts in keratinocyte-conditioned culture medium led to a 5.7-fold increase in the level of matrix metalloproteinase-1. Virtually all of the matrix metalloproteinase-1 - inducing activity could be related to agonists acting through members of the epidermal growth factor receptor family or to agonists acting through the interleukin-1 receptor. The same keratinocyte-conditioned medium also induced a modest increase in fibroblast proliferation (approximately 1.8-fold). Growth-stimulating activity could be attributed to epidermal growth factor receptor (but not interleukin-1 receptor) function. In fibroblasts exposed to keratinocyte-conditioned medium, mitogen-activated protein kinase signalling through both the extracellular signal-related kinase pathway and p38 pathway occurred. When recombinant epidermal growth factor or recombinant interleukin-1beta were used as a control, they induced mitogen-activated protein kinase signalling consistent with the combined effects of epidermal growth factor receptor - specific and interleukin-1 receptor - specific agonists in keratinocyte-conditioned medium. Recombinant epidermal growth factor stimulated both matrix metalloproteinase-1 induction and proliferation while recombinant interleukin-1beta stimulated matrix metalloproteinase-1 elaboration but not fibroblast growth. An inhibitor of extracellular signal-related kinase pathway signalling (U0126) blocked induction of matrix metalloproteinase-1 production induced by keratinocyte-conditioned medium (as well as by epidermal growth factor or interleukin-1beta), and also inhibited proliferation. A p38 signalling inhibitor (SB203580) blocked matrix metalloproteinase-1 elaboration induced by keratinocyte-conditioned medium or interleukin-1beta, but did not inhibit matrix metalloproteinase-1 elaboration or cell growth induced by epidermal growth factor. These data indicate that keratinocyte-fibroblast interactions are mediated by multiple stimulating agents acting on specific receptors to induce signalling through different mitogen-activated protein kinase pathways leading to altered expression of key biological functions.

Carrier Proteins↗
PubMed2005

Polymorphisms in the promoter regions of the matrix metalloproteinases-1, -3, -7, and -9 and the risk of epithelial ovarian cancer in China.

PURPOSE: To investigate the association of single nucleotide polymorphisms (SNP) in the promoter region of the matrix metalloproteinases-1 -1607bp1G/2G, matrix metalloproteinases-3 -1171bp5A/6A, matrix metalloproteinases-7 A-181G and matrix metalloproteinases-9 C-1562T with susceptibility to ovarian cancer in a population of North China. EXPERIMENTAL DESIGN: We analyzed four different functional promoter polymorphisms in the respective genes by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) in a sample of patients with epithelium ovarian cancer and control women, all from North China. RESULTS: No significant difference was detected between the patient and control groups in genotype and allelotype distribution of MMP-1, MMP-3, MMP-9 of the polymorphisms studied. However, the genotype and allelotype of the MMP-7 distribution in ovarian cancer patients were significantly different from that in healthy controls. The frequency of the -181G allele of MMP-7 in patients was significantly higher than that in healthy controls women (8.2% vs. 2.8%, P = 0.002). Compared to the A/A genotype, the genotypes with the -181G allele (A/G + G/G) significantly increased susceptibility to ovarian cancer, with adjusted odds ratio [OR] = 3.53 95% confidence interval [CI] [1.58 to 7.89]. CONCLUSIONS: The study suggested that a possible association between the MMP-7 A/G polymorphism with susceptibility to epithelium ovarian cancer, but there is no support for an association of the selected MMP-1 1G/2G, MMP-3 5A/6A, and MMP-9 C/T polymorphisms with the risk for ovarian cancer.

Adult↗
PubMed1999

Marmoset monkey trophoblastic tissue growth and matrix metalloproteinase secretion in culture.

Marmoset monkey blastocysts maintained in culture produced trophoblastic vesicles up to 4 mm in diameter that were subdivided into fragments and subcultured to produce new vesicles. These tissues are composed of an outer layer of trophoblast-like cells and an inner layer of endoderm-like cells, and resemble a blastocyst wall. When such vesicles were cultured in serum-free medium for 14 days, they increased in size but there was no significant difference in their protein content at the end of culture. The proliferation index, measured by BrdU incorporation, varied considerably within and between vesicles. The purpose of this investigation was to determine which matrix metalloproteinases are secreted by marmoset monkey trophoblastic tissue in vitro, and the effect of extracellular laminin on this secretion. It was determined by zymography that the vesicles secreted matrix metalloproteinase 2, but not matrix metalloproteinase 9, and that matrix metalloproteinase 2 was secreted as the proenzyme (72 kDa). Matrix metalloproteinases 1, 3 and 7 were not detectable in the culture medium. The addition of laminin (5-20 micrograms ml-1), either as a substrate or in solution in the medium, did not have a consistent effect on matrix metalloproteinase 2 secretion during the culture period. The vesicles were found to express both matrix metalloproteinases 2 and 9 in both types of cell when examined by immunohistochemistry. The expression of matrix metalloproteinase 9 in the vesicles, but the absence of its secretion, indicates that specific factors, possibly of endometrial origin, may be required for inducing secretion.

Analysis of Variance↗
PubMed2002

Regulation of matrix metalloproteinase expression by estrogen in fibroblasts that are derived from the pelvic floor.

OBJECTIVE: The purpose of this study was to determine whether estrogen suppresses matrix metalloproteinase-2 and -9 proenzyme expression by fibroblasts that are derived from the supportive connective tissue of the pelvic floor. STUDY DESIGN: A primary fibroblast culture that was developed from a biopsy specimen of the arcus tendineus was treated with interleukin-1 beta (10-15 ng/mL), transforming growth factor-beta 1 (5-15 ng/mL), 17 beta-estradiol (10(-9)-10(-7) mol/L), and Imperial Chemical Industries (ICI) 182 780 (10(-8)-10(-6) mol/L). Cellular and extracellular protein were analyzed by Western blotting and substrate zymography, respectively, for the effect of each treatment on the amount of pro-matrix metalloproteinase-2 and -9 and the membrane type 1 matrix metalloproteinase protein. RESULTS: Both cellular and extracellular pro-matrix metalloproteinase-2 protein were increased by transforming growth factor-beta1 (P =.01) and decreased by estradiol (P <.001) and ICI 182 780 (P =.02 and.002, respectively). Membrane type 1 matrix metalloproteinase was not affected by estradiol, ICI 182 780, interleukin-1 beta, or transforming growth factor-beta 1. Extracellular pro-matrix metalloproteinase-9 was increased by the cytokines interleukin-1 beta (P <.001) and transforming growth factor-beta1 (P <.001) and decreased by estradiol (P <.001) and ICI 182 780 (P <.001). CONCLUSION: The proenzymes of the tissue-degrading matrix metalloproteinases -2 and -9 are decreased by 17-beta estradiol and ICI 182 780.

Adult↗
PubMed2004

Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives.

Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.

Animals↗
PubMed2005

Proteolysis of cell-surface tissue transglutaminase by matrix metalloproteinase-2 contributes to the adhesive defect and matrix abnormalities in thrombospondin-2-null fibroblasts and mice.

Thrombospondin (TSP)-2-null dermal fibroblasts display an attachment defect that results from increased matrix metalloproteinase (MMP)-2 levels in their conditioned media. To investigate the molecular mechanisms responsible for this defect, we analyzed the activity of tissue transglutaminase (tTG) in TSP-2-null dermal fibroblasts and in tissues of TSP-2-null mice. tTG functions as a co-receptor for beta1 and beta3 integrins and stabilizes extracellular matrix proteins by introduction of isopeptide cross-links. Cell-surface tTG activity was reduced in TSP-2-null cells (0.50 +/- 0.05 arbitrary units versus 0.84 +/- 0.07 for wild type; P < or = 0.05), and addition of MMP-2 to the culture medium of wild-type cells caused a 35% reduction in cell-surface tTG activity. tTG was susceptible to proteolysis by MMP-2 in vitro, and addition of the MMP inhibitor TIMP-2 to TSP-2-null cells restored tTG activity (0.3 +/- 0.08 for untreated cells; 0.71 +/- 0.09 with TIMP-2). TSP-2-null mice had reduced tTG activity in skin, as measured by incorporation of fluorescein isothiocyanate-labeled cadaverine, and a threefold increase in acetic acid-extracted dermal collagen. Furthermore, isopeptide cross-links were reduced in both uninjured skin and in excisional wounds of TSP-2-null mice, as determined by morphometric immunohistochemical analysis, indicating that isopeptide cross-links are important for the stabilization of the collagenous matrix in dermis. These findings provide a mechanism for the reduced adhesion of TSP-2-null fibroblasts and an explanation for the increased collagen solubility and fragility of TSP-2-null skin.

Animals↗
PubMed2003

Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages.

Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix (ECM) components during normal and pathogenic tissue remodeling. Inappropriate expression of these enzymes contributes to the development of vascular pathology, including atherosclerosis. MMP-9 is expressed in its active form in atherosclerotic lesions and is believed to play an important role in vascular remodeling, smooth muscle cell migration, and plaque instability. We demonstrate here that the liver X receptors (LXRs) LXRalpha and LXRbeta inhibit basal and cytokine-inducible expression of MMP-9. Treatment of murine peritoneal macrophages with the synthetic LXR agonists GW3965 or T1317 reduces MMP-9 mRNA expression and blunts its induction by pro-inflammatory stimuli including lipopolysaccharide, interleukin-1beta, and tumor necrosis factor alpha. In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands. We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXRalphabeta null mice. Analysis of the 5'-flanking region of the MMP-9 gene indicates that LXR/RXR heterodimers do not bind directly to the MMP-9 promoter. Rather, activation of LXRs represses MMP-9 expression, at least in part through antagonism of the NFkappaB signaling pathway. These observations identify the regulation of macrophage MMP-9 expression as a mechanism whereby activation of LXRs may impact macrophage inflammatory responses.

Animals↗
PubMed2005

Matrix metalloproteinases in corneal inflammation.

Matrix metalloproteinases (MMPs) are a family of calcium-dependent, zinc-containing endoproteinases capable of degrading the extracellular matrix and basement membrane. Many inflammatory stimuli, such as wound healing, ultraviolet, hyperosmolarity, and stress, can stimulate production of inflammatory cytokines and a variety of MMPs, including gelatinases, collagenases, and stromelysins. Pro-inflammatory cytokines and growth factors can further promote the production of MMPs. Thus, MMPs participate in and promote the inflammation process. MMP-9 may be a most important amplifying factor for corneal inflammation. Mitogen activated protein kinases are involved in MMPs amplified inflammation. These pathway studies provide new therapeutic potential to block MMP mediated inflammation.

Journal Article↗
PubMed1997

Membrane type-1 matrix metalloproteinase in human ocular tissues.

PURPOSE: Membrane type-1 matrix metalloproteinase (MT1-MMP) (MMP-14) (EC 3.4.24.xx) is involved in the activation of progelatinase A (MMP-2) (EC 3.4.24.24). MMP-2 is present at least in the interphotoreceptor matrix and vitreous. The purpose of this study was to determine the distribution of MT1-MMP, and MMP-2, in human ocular tissues. METHODS: The distribution of MT1-MMP and MMP-2 was investigated in vitreous and in membrane extracts from eye tissues obtained from postmortem human eyebank eyes. Western blot analysis was performed using mouse monoclonal anti-MT1-MMP and anti-MMP-2 antibodies. RESULTS: MT1-MMP was found in sclera, cornea, lens, choroid, retinal pigment epithelium (RPE) and retina. MMP-2 was found in sclera, cornea, choroid, vitreous, RPE and retina but was absent from lens. CONCLUSION: We provide the first evidence for the presence and distribution of membrane-type-1 matrix metalloproteinase in human ocular tissues. MT1-MMP may be responsible for the activation of progelatinase A in many ocular extracellular matrices in a manner similar to that exhibited in other systems.

Animals↗
PubMed2006

Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia.

UNLABELLED: Matrix metalloproteinases (MMPs) degrade the extracellular matrix and contribute to LPS-induced gastric injury. MMPs are closely modulated by their activators, membrane type-MMP (MT-MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). As LPS-induced gastric injury is mediated in part by iNOS, and NO modulates MMP production in vitro, we hypothesized that NOS inhibition would similarly modulate LPS-induced gastric MMP production. Therefore, the purpose of these studies was to compare the effects of selective and nonselective NOS inhibition on LPS-induced gastric MMP production. METHODS: Sprague-Dawley rats were given either the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg, s.c.), a selective iNOS inhibitor, aminoguanidine (45 mg/kg, i.p.) or L-N-iminoethyl-lysine (L-NIL; 10 mg/kg, i.p.), or vehicle 15 min before saline or LPS (20 mg/kg, i.p.) and killed 24 h after LPS administration. Stomachs were assessed for macroscopic injury (computed planimetry), and gastric mucosal MMP production was assessed by gelatin zymography, in situ zymography, and Western analysis for MMP-2, MT1-MMP, and TIMP-2. (n > or = 4/group; ANOVA). RESULTS: Aminoguanidine treatment decreased LPS-induced macroscopic gastric injury as well as MMP-2 and MT1-MMP protein production while having no effect on TIMP-2 protein levels. L-NIL similarly attenuated the induction of MMP-2 and MT1-MMP by LPS. L-NAME failed to attenuate LPS induced gastric injury or MT1-MMP protein induction and increased MMP-2 levels. L-NAME similarly had no effect on gastric TIMP-2 production. CONCLUSIONS: Selective iNOS inhibition decreases gastric MMP-2 activity after LPS administration, whereas nonselective inhibition increases MMP-2 levels. The ability of selective iNOS inhibition to ameliorate LPS-induced gastric injury may be due in part to its inhibition of active MMP-2 production, whereas nonselective NOS inhibitors increase MMP-2 levels and maintain gastric injury after LPS administration.

Animals↗
PubMed1999

Matrix-metalloproteinases in bronchopulmonary carcinomas.

Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the extracellular matrix and therefore participate in tumoural invasion. MMPs, especially gelatinases A and B, MT1-MMP, the activator of gelatinase A, and stromelysin-3 were found overexpressed in many cancers including bronchopulmonary carcinomas. In vivo observations revealed that fibroblasts are the principal source of production of MMPs. Some of these enzymes such as MT1-MMP and stromelysin 3, displayed a focal stromal localisation near preinvasive and invasive tumour clusters. Furthermore, some tumour cell lines were shown to stimulate the expression of MT1-MMP by fibroblasts. All these in vivo and in vitro results suggest that certain tumour cells produce diffusible factors which could influence the MMP stromal expression. Among these factors, the TCSF (Tumor Collagenase Stimulatory Factor) which is known to upregulate some MMPs in vitro could be a good candidate for this stromal regulation, since it is produced by bronchial tumour cells in vivo. In this review, we address such a cooperation between tumour and stromal cells for the production of MMPs and emphasize their necessity for tumoural progression in bronchopulmonary carcinomas.

Bronchial Neoplasms↗
PubMed1996

Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond.

Matrix metalloproteinases (MMPs) can degrade a number of proteins that constitute the extracellular matrix. Previous studies have shown that atherosclerotic plaques contain substantial amounts of fibrin(ogen)-related antigen, and more recently, MMPs have been identified in such lesions. The hypothesis that MMPs play a role in the degradation of fibrinogen (Fg) and cross-linked fibrin (XL-Fb) was investigated. Fibrinogen became thrombin-unclottable when treated with matrix metalloproteinase 3 (MMP-3, stromelysin 1) but not with matrix metalloproteinase 2 (MMP-2, gelatinase A). Incubation of XL-Fb clots (made with 125I-Fg) with MMP-3 resulted in complete lysis after 24 h. A D monomer-like fragment was generated by MMP-3 degradation of fibrinogen, XL-Fb, and fragment DD. Immunoreactivity with monoclonal antibody (MoAb)/4-2 (anti-gamma 392-406) but not with MoAb/4A5 (anti-gamma 397-411) suggested that a major cleavage site was within the sequence participating in the cross-linking of two gamma-chains. NH2-terminal sequence analysis of they gamma-chain of the D monomer-like fragment and of a dipeptide isolated from the MMP-3 digest of XL-fibrin identified the hydrolysis of the gamma Gly 404-Ala 405 peptide bond. These data indicate that the degradation of Fg and XL-Fb by MMP-3 is specific and different from plasmin. This mechanism of fibrinolysis might be of relevance in wound healing, inflammation, atherosclerosis, and other pathophysiological processes.

Amino Acid Sequence↗