Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate a potential role for stromelysin-1 (MMP-3) in the development and progression of atherosclerotic lesions and aneurysm formation, mice with a deficiency of apolipoprotein E (ApoE(-/-):MMP-3(+/+))) or with a combined deficiency of apoE and MMP-3 (ApoE(-/-):MMP-3(-/-)) were kept on a cholesterol-rich diet for 30 weeks. Atherosclerotic lesions throughout the thoracic aorta were significantly larger in ApoE(-/-):MMP-3(-/-) than in ApoE(-/-):MMP-3(+/+) mice (P<0.05) and contained more fibrillar collagen (P<0.01). Aneurysms in the thoracic and abdominal aortas were less frequent in ApoE(-/-):MMP-3(-/-) than in ApoE(-/-):MMP-3(+/+) mice (8.5+/-1.7% vs 14+/-2.1% of sections, mean+/-SD, P<0.01). Immunocytochemistry revealed enhanced accumulation of macrophages in atherosclerotic lesions of ApoE(-/-):MMP-3(+/+) mice (P<0.01) and expression of urokinase-type plasminogen activator (u-PA) and MMP-3 colocalizing with macrophages. Zymography confirmed the presence of u-PA and MMP-3 activity in extracts of atherosclerotic aortas. These data suggest that plasmin, generated by macrophage-secreted u-PA, activates pro-MMP-3 produced by accumulated macrophages. MMP-3 activity may then contribute to a reduction of plaque size, possibly by degradation of matrix components, and promote aneurysm formation by degradation of the elastica lamina.
Arterioscler Thromb Vasc Biol 2001 Sep
PMID:Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. 1155 61

Vascular endothelial growth factor (VEGF), a potent angiogenic mitogen, plays a crucial role in angiogenesis under various pathophysiological conditions. We have recently demonstrated that VEGF(165), one of the VEGF isoforms, binds connective tissue growth factor (CTGF) and that its angiogenic activity is inhibited in the VEGF(165).CTGF complex form (Inoki, I., Shiomi, T., Hashimoto, G., Enomoto, H., Nakamura, H., Makino, K., Ikeda, E., Takata, S., Kobayashi, K. and Okada, Y. (2002) FASEB J. 16, 219-221). In the present study, we further examined the susceptibility of the VEGF(165).CTGF complex to matrix metalloproteinases (MMP-1, -2, -3, -7, -9, and -13), ADAMTS4 (aggrecanase-1), and serine proteinases, and evaluated the recovery of the angiogenic activity of VEGF(165) after the treatment. Among the MMPs, MMP-1, -3, -7, and -13 processed CTGF of the complex into the major NH(2)- and COOH-terminal fragments, whereas VEGF(165) was completely resistant to the MMPs. On the other hand, elastase and plasmin cleaved both CTGF and VEGF(165) of the complex, but they were completely resistant to ADAMTS4. By digestion of the immobilized VEGF(165).CTGF complex with MMP-3 or MMP-7, both NH(2)- and COOH-terminal fragments of CTGF were dissociated and released from the complex into the liquid phase. The in vitro angiogenic activity of VEGF(165) blocked in the VEGF(165).CTGF complex was reactivated to original levels after CTGF digestion of the complex with MMP-1, -3, and -13. Recovery of angiogenic activity was further confirmed by in vivo angiogenesis assay using a Matrigel injection model in mice. These results demonstrate for the first time that CTGF is a substrate of MMPs and that the angiogenic activity of VEGF(165) suppressed by the complex formation with CTGF is recovered through the selective degradation of CTGF by MMPs. MMPs may play a novel role through CTGF degradation in VEGF-induced angiogenesis during embryonic development, tissue maintenance, and/or pathological processes of various diseases.
J Biol Chem 2002 Sep 27
PMID:Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. 1211 4

Early gestation mammalian fetuses possess the remarkable ability to heal cutaneous wounds in a scarless fashion. Over the past 20 years, scientists have been working to decipher the mechanisms underlying this phenomenon. Much of the research to date has focused on fetal correlates of adult wound healing that promote fibrosis and granulation tissue formation. It is important to remember, however, that wound repair consists of a balance between tissue synthesis, deposition, and degradation. Relatively little attention has been paid to this latter component of the fetal wound healing process. In this study, we examined the ontogeny of ten matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in nonwounded fetal rat skin and fibroblasts as a function of gestational age. We used a semiquantitative polymerase chain reaction protocol to analyze these important enzymes at time points that represent both the scarless and scar-forming periods of rat gestation. The enzymes evaluated were collagenase-1 (MMP-1), stromelysin-1 (MMP-3), gelatinase A (MMP-2), gelatinase B (MMP-9), membrane-type matrix metalloproteinases (MT-MMPs) 1, 2, and 3, and TIMPs 1, 2, and 3. Results demonstrated marked increases in gene expression for MMP-1, MMP-3 and MMP-9 that correlated with the onset of scar formation in nonwounded fetal skin. Similar results were noted in terms of MMP-9 gene expression in fetal fibroblasts. These results suggest that differences in the expression of these matrix metalloproteinases may have a role in the scarless wound healing phenotype observed early in fetal rat gestation. Furthermore, our data suggest that the differential expression of gelatinase B (MMP-9) may be mediated by the fetal fibroblasts themselves.
Plast Reconstr Surg 2002 Sep 01
PMID:Matrix metalloproteinases and the ontogeny of scarless repair: the other side of the wound healing balance. 1217 42

Using a progesterone receptor antagonist, onapristone/ZK 98.299, we examined the in-vivo effects of progesterone on the function of uterine cervix during pregnancy. Onapristone was intravenously administered to pregnant rabbits on day 20 post coitum. After 24 h, the antiprogesterone increased the wet weight of the uterine cervix and decreased the DNA concentration in the cervix. In-situ hybridization also indicated that antiprogesterone augmented the expression of matrix metalloproteinase (MMP)-3/stromelysin-1 mRNA in the uterine cervix. These changes are very similar to those observed and reported thus far in ripened and dilated uterine cervix. These results suggest that during pregnancy, progesterone closely participates in the maintenance of the function of uterine cervix by preventing the production of MMPs and thereby destruction of extracellular matrix, and thus add support to the theory that antiprogesterone has the potential to accelerate for the uterine cervical ripening and dilatation.
Biol Pharm Bull 2002 Sep
PMID:An antiprogesterone, onapristone, enhances the gene expression of promatrix metalloproteinase 3/prostromelysin-1 in the uterine cervix of pregnant rabbit. 1223 Jan 24

Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-Cys-Gly-Val-Pro-Asp-NH2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.
Eur J Biochem 2002 Sep
PMID:Inhibition of human MDA-MB-231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen. 1223 May 59

Matrix metalloproteinases (MMPs) comprise family proteolytic enzymes that degrade extracellular matrix components and therefore play an important role in tumour cell invasion and cancer metastasis. Overexpression of matrix metalloproteinase 3 (MMP-3 or stromelysin 1) gene has been demonstrated in various types of cancers and high level of MMP-3 protein in tumour is a poor prognostic factor for patients. The insertion (6A)/deletion (5A) polymorphism (5A/6A polymorphism) located at the promoter of the MMP-3 gene may have functional significance in the regulation of its expression. In the present work the distribution of genotypes and frequencies of alleles of the 5A/6A polymorphism in subjects with ovarian cancer were investigated. Paraffin embedded tumour tissues were obtained from 100 women with ovarian cancer. The genotypes of 5A/6A polymorphism were determined by PCR amplification using the allele specific primers. The distribution of the genotypes of the 5A/6A polymorphism in both control and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. Additionally, there were no significant differences (p > 0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage. The results suggest that the 5A/6A polymorphism of MMP-3 gene may not be linked with appearance and development to ovarian cancer.
J Exp Clin Cancer Res 2002 Sep
PMID:The promoter polymorphism of the matrix metalloproteinase 3 (MMP-3) gene in women with ovarian cancer. 1238 78

Glucosamine inhibits recombinant human interleukin-1 stimulated cartilage degradation in equine cartilage explants. Recently, recombinant equine interleukin-1 has been cloned and purified. Therefore, the objective of this study was to characterise the effects of glucosamine on indices of cartilage degradation in recombinant equine IL-1beta-stimulated equine articular cartilage explants. Cartilage discs were harvested from the weight-bearing region of the articular surface of the antebrachiocarpal and middle carpal joints of horses (age 2-8 years) and cultured under standard conditions. Explants were exposed to recombinant equine interleukin-1beta (reIL-1beta) on Days 1-4 in the presence or absence of glucosamine (0.25, 2.5 or 25 mg/ml), with appropriate controls. Nitric oxide, prostaglandin E2, sulphated proteoglycan, stromelysin and gelatinase/collagenase activity released into conditioned media and total tissue proteoglycan content were measured as indicators of cartilage catabolism. Glucosamine inhibited cartilage catabolic responses in a dose dependent manner that was statistically significant at a dose of 0.25 mg/ml for stromelysin activity and 2.5 mg/ml for collagenase/gelatinase activity. At 25 mg/ml glucosamine also prevented IL-1beta-induced increases in nitric oxide production, prostaglandin E2 and proteoglycan release to media. Glucosamine prevents equine articular cartilage degradation experimentally induced by reIL-1beta in vitro. These data provide further support for the use of glucosamine in treatment or prevention of cartilage loss in athletic horses.
Equine Vet J Suppl 2002 Sep
PMID:Effect of glucosamine on interleukin-1-conditioned articular cartilage. 1240 90

Matrix metalloproteinases (MMPs) are central to tissue remodelling; however, little is known about the temporal pattern and differential regulation of hepatic MMP expression in the course of chronic human liver disease. Using quantitative reverse transcription-PCR ELISA assays, we studied hepatic mRNA expression of MMP-1, -2, -3, -7, -9, -10, -11, -13 and -14 in patients with chronic hepatitis C and hepatitis C virus-induced end-stage liver cirrhosis and controls. Results were compared with histology, hepatic expression of tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3, procollagen types I and IV, laminin, and with circulating protein levels of hyaluronate, TIMP-1 and -2 and MMP proenzymes, as measured by ELISA. The impact of the MMP-3(-1171) promoter polymorphism on hepatic MMP-3 expression was analysed. Hepatic mRNA expression data identified differentially regulated groups of MMPs during the course of chronic hepatitis C, showing either steadily increasing mRNA expression with disease progression (MMP-1, -2, -7 and -14) or transiently elevated expression (MMP-9, -11 and -13). The first group closely correlated to the parameters of fibrogenesis. Hepatic MMP-3 expression was unrelated to disease stage, but was determined by the MMP-3(-1171) promoter polymorphism. In conclusion, MMP expression during the course of chronic hepatitis C appears to be a closely regulated process, with different clusters of coordinately regulated MMP genes being identified.
Clin Sci (Lond) 2003 Sep
PMID:Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis. 1276 Jul 42

Tumor invasiveness is an intrinsic feature of most glial tumors that accounts for their malignant and locally destructive nature. We evaluated the subcutaneous (sc) tumorigenicity and in vivo invasiveness of 9 astrocytoma cell lines together with their respective metalloprotease activity in order to establish their biologic behavior and malignant potential. Invasiveness was assessed with an in vivo invasion assay using tracheal xenotransplants subcutaneously implanted into Scid mice. This assay permitted us to evaluate the penetration of tumor cells into the transplanted deepithelialized tracheas previously inoculated with either normal primary glial cells or with astrocytoma-derived cell lines. Although only 2 cell lines were tumorigenic after sc inoculation, 5 out of 9 tumor cell lines were tumorigenic in the tracheal graft system. The astrocytoma cell lines showed varying levels of penetration into the tracheal wall. The tumor lines GOS3, M059K, CCFSTTG1 and A172, as well as primary normal astrocytes, were nontumorigenic and noninvasive in this experimental model. LN405, SW1088 and SW1783 cells that were not tumorigenic as sc xenotransplants, on the other hand, grew well in the tracheal graft system showing low levels of in vivo invasiveness. U87MG and U118MG cells were tumorigenic as sc xenotransplants and showed high levels of invasiveness. In parallel to these in vivo studies, the constitutive levels of secreted gelatinases and stromelysins (MMP-3 and MMP-11) were investigated using conditioned media submitted to gelatin or casein-substrate zymography and Western blot analysis. Neither the gelatinases (MMP-2 and MMP-9) nor MMP-11 showed a direct correlation with the levels of in vivo tumor cell invasiveness. Conversely, secretion of MMP-3 correlated closely with tumorigenicity and invasiveness. In vitro tumor cell invasiveness was significantly reduced after incubation with the metalloproteinase inhibitor GM6001. This positive correlation between MMP-3 and the depth of tracheal wall penetration led us to conclude that the invasive properties of brain tumor cells may be due to the direct or indirect proteolytic effects of MMP-3 on extracellular matrix (ECM) macromolecules and that this enzyme might be a potential target for future therapies.
Int J Cancer 2003 Sep 20
PMID:Stromelysin-1/matrix metalloproteinase-3 (MMP-3) expression accounts for invasive properties of human astrocytoma cell lines. 1286 26

We surveyed the expression of 557 cancer-related genes in 15 cases of well-differentiated OSCC by cDNA microarray analysis. To identify potential biomarkers for lymph node metastasis, all microarray data were compared by the Mann-Whitney test and the significance analysis of microarrays between OSCCs with and those without lymph node metastasis. The tissues of OSCCs with lymph node metastasis exhibited increased expression levels of MMP-1, MMP-3, uPA, integrin-alpha3, paxillin, tenascin C and IL-6 transcripts. All of these genes were included in common clusters on the Cluster/TreeView analysis, implying that functional gene groups of proteolytic enzymes and integrin-related molecules are involved in cervical lymph node metastasis. The results of RTQ-PCR for differentially expressed genes were in accord with those of cDNA microarray analyses, suggesting that the data obtained by microarray gene expression analyses were valid. Consistent with cooperative expression patterns, immunohistochemical analyses demonstrated that products of MMP-1, MMP-3 and uPA were colocalized to components of the neoplastic stroma, particularly mononuclear inflammatory cells with well-developed eosinophilic cytoplasm. Our results suggest that expression levels of molecules involved in tissue remodeling and cell-ECM adhesion, especially MMP-1 and integrin-alpha3, can provide an accurate biomarker system for predicting the risk of cervical lymph node metastasis in OSCC.
Int J Cancer 2003 Sep 20
PMID:Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis. 1286 27


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