Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell-derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-alpha and TGF-beta 1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-alpha mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-beta 1, TNF-alpha, and IL-1 alpha. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
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PMID:Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1. 897 86

Scleritis is a sight-threatening inflammatory disorder of the eye characterized by the degradation of scleral matrix. Matrix metalloproteinases (MMPs) are ubiquitous proteolytic enzymes important in physiological and pathological processes, the activity of which is stringently controlled by the action of a family of natural antagonists, the tissue inhibitors of matrix metalloproteinases (TIMPs). We hypothesized that enhanced expression of MMPs, without the negative regulatory influence of TIMPs, may be a key feature of tissue destruction in inflammatory eye diseases, such as scleritis. The aim of this study was to localize and characterize cells expressing MMPs and TIMPs in sclera affected by necrotizing scleritis and, in a parallel study, to establish whether cytokines modulate MMP expression in cultured human scleral fibroblasts. In situ hybridization and immunohistochemical analyses indicated that resident scleral fibroblasts as well as inflammatory cells such as macrophages and T lymphocytes express stromelysin, gelatinase B, and TIMP-1 in necrotizing scleritis tissue. In addition, cytoplasmic immunoreactivity for tumor necrosis factor-alpha, an inducer of MMPs, was detected in infiltrating inflammatory cells. Cultured scleral fibroblasts stimulated with the combination of interleukin-1 alpha plus tumor necrosis factor-alpha increased TIMP-1 mRNA twofold above constitutive levels. By contrast, these cytokines induced a sevenfold increase in the steady-state levels of stromelysin mRNA. Using Western blotting, stromelysin and TIMP-1 protein production paralleled mRNA induction in cytokine-stimulated human scleral fibroblasts. Culture supernatants harvested from cytokine-stimulated human scleral fibroblasts were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis gelatin substrate zymography. Our results revealed a prominent 92-kd gelatinolytic band corresponding to gelatinase B, which was inducible with interleukin-1 alpha. These data provide evidence for our hypothesis, that an imbalance between enzyme/inhibitor ratios may be the underlying mechanism of the tissue destruction characteristic of scleritis. Our results demonstrate the potential involvement of MMPs and their modulation by cytokines produced by infiltrating inflammatory cells in destructive ocular inflammation.
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PMID:Increased expression of matrix metalloproteinases in vivo in scleritis tissue and in vitro in cultured human scleral fibroblasts. 903 78

The expression of extracellular-matrix (ECM)-degrading proteases has been shown to be necessary for invasion of tumor cells into surrounding tissue. For several tumor types, overexpression of these proteases is dependent upon interactions with adjacent fibroblast cell populations. We previously demonstrated activation of matrix metalloprotease (MMP) and urokinase-type plasminogen activator (uPa) expression in a coculture model consisting of squamous cell carcinoma cells (SCC) with dermal fibroblasts. In the present study we have examined whether melanocytes, which are known to interact closely with keratinocytes of the basal epidermal layer, might influence ECM-degrading protease expression in SCC cells as well. Upon coculture of the human SCC cell line II-4 with the nontumorigenic mouse melanocyte cell line Melan-a or treatment of II-4 cells with Melan-a conditioned media, induction of expression of the MMP matrilysin and uPa was observed. In contrast, no induction was observed for stromelysin-1 or 92-kDa type IV collagenase. Matrilysin/uPa-inducing activity was found to act at the level of gene transcription for both matrilysin and uPa and was ubiquitously expressed among six different human melanocytic cell strains/lines, ranging from primary normal melanocytes to cell lines established from metastatic melanoma lesions. These data demonstrate that melanocytic cells can exert a paracrine influence in SCC cells on the expression of specific proteases involved in ECM turnover and tumor invasiveness.
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PMID:Melanocyte mediated paracrine induction of extracellular matrix degrading proteases in squamous cell carcinoma cells. 905 12

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.
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PMID:Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. 906 95

Decidual and placental relaxins have been proposed as autocrine/ paracrine hormones in the remodeling of collagen in the amnion and chorion in the last weeks of pregnancy. The matrix metalloproteinase-1 (MMP-1) is a key enzyme in the degradation of the interstitial collagens which predominate in the fetal membranes. Distribution of the MMP-1 gene and of the MMP-1 protein was shown by in situ hybridization and immunolocalization, respectively, in amnion, chorion, and decidua collected from patients before the onset of spontaneous labor. The distribution of MMP-1 in the chorionic cytotrophoblast and decidua coincided with that of the human relaxin receptor, detected by tissue section autoradiography in tissues collected at the same stage of pregnancy. Fetal membrane explants were used to study the effect of exogenous human relaxin H2. These responded by a dose-dependent increase in expression of the MMP-1 gene, in its secreted protein, and in its enzyme activity in the medium. A similar dose-dependent increase in the tissue plasminogen activator (tPA) gene and protein upon exposure of the explants to relaxin H2 suggested a coordinated cascade system, resulting in increases in secreted activities of MMP-1, MMP-3 (stromelysin), and MMP-9 (gelatinase B). There was no effect on the genes or proteins for MMP-2 (gelatinase A) or tissue inhibitor of metalloproteinase-1 (TIMP-1), showing the specificity of the response. This coordinated regulation by relaxin H2 of tPA, MMP-1, MMP-3, and MMP-9 would result in more complete degradation of the fetal membrane extracellular matrix components.
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PMID:An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator. 909 59

Interstitial collagen types I and III are the predominant collagens in the amniotic and chorionic connective tissues. However, this matrix also contains proteoglycans, fibronectin, laminin, and elastin, which together with the collagens may undergo partial degradation prior to fetal membrane rupture at term. In this study, stromelysin (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were immunolocalized in fetal membranes obtained at term prior to labor. MMP-3 stained the cells of the amniotic epithelium, fibroblasts and macrophages of the amniotic and chorionic matrix, and those of the chorionic cytotrophoblast; there was no staining in the maternal decidua. TIMP-1 showed a similar staining pattern, except that the staining was darker in some amniotic epithelial cells and was present in the maternal decidua. The maternal decidua produces the two human relaxins H1 and H2; the latter, when incubated with explants of human fetal membranes, caused a dose-dependent and significant increase in expression of the MMP-3 gene and its secreted protein into the media. A significant effect of relaxin H2 on 92-kDa gelatinase (MMP-9) gene expression was also shown--an effect requiring poly(A)+ RNA rather than total RNA. Both relaxin H1 and H2 caused a significant increase in secretion of MMP-9 protein and its enzyme activity in the media. The magnitude of the effects of the two relaxins was similar, in contrast to findings from other biological studies in which relaxin H2 was shown to be more active. Neither of the relaxins had any effect on 72-kDa gelatinase (MMP-2) activity or on the TIMP-1 protein or its activity. This study suggests that local relaxins may be involved in the degradation of the complex fetal membrane extracellular matrix and may cause activation of an enzyme cascade resulting in fully activated MMP-9. Such effects could be important in the degradative pathways occurring in the amnion and chorion in the peripartal period.
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PMID:An autocrine/paracrine role of human decidual relaxin. II. Stromelysin-1 (MMP-3) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). 909 60

We have investigated the role of proteinases in the developmental program of bone, cartilage, tongue muscle and epithelial differentiation and remodeling in the mandibular arch during murine embryogenesis. Expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) was tissue-specific with little or no expression in the epithelium of tooth buds, tongue or oral cavity. Gelatinase A mRNA transcripts were strongly expressed in the perichondrium of Meckel's cartilage and mesenchymal areas of embryonic day 13-15 mandibles, whereas gelatinase B, collagenase-3, TIMP-1 and TIMP-2 mRNA were found primarily in the ossifying areas of the mandibles. The skeletal muscle of the tongue expressed stromelysin-3, TIMP-2 and TIMP-3 mRNA while stromelysin-3, TIMP-2 and gelatinase A were seen in the overlying connective tissue layer. Gelatinase A, gelatinase B, stromelysin-1, urokinase, TIMP-1 and TIMP-2 mRNA and protein activities were also detected in cultured mandibular explants. Culture of day 10 mandibular explants with a hydroxamic acid metalloproteinase inhibitor, but not with inhibitors of metalloendopeptidases (thiorphan and phosphoramidon), serine proteinases (aprotinin), cysteine proteinases (leupeptin) and urokinase (amiloride), altered mandibular morphogenesis dramatically. Development of the tongue (glossogenesis) and cartilage, but not bone or teeth was affected. Formation of the oral sulcus and fusion of the two epithelia of the medial sulcus were inhibited, and number and migration of myoblasts decreased. The resulting 'tongue-tied phenotype' indicates that MMPs are involved in epithelial morphogenesis and the migration of myoblasts to the region of the tongue. Development of the anterior segment of Meckel's cartilage was also inhibited and proteoglycan content of the cartilage was reduced by inhibiting MMPs. Our data suggest that matrix metalloproteinases play a pivotal role in the morphogenesis of structures derived from epithelium (oral sulcus), cranial paraxial mesoderm (tongue) and cranial neural crest (Meckel's cartilage).
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PMID:Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. 910 68

To study the role of matrix metalloproteinases (MMPs) in early vertebrate development, we cloned cDNAs for six different MMPs from the frog Xenopus laevis embryos at different stages of development and describe here a novel MMP called XMMP. Xenopus XMMP has 604 amino acids including a putative signal peptide of 22 residues. At the carboxyl-terminal end of the propeptide, XMMP has a 37-amino acid-long insertion domain containing a segment that is 38% identical with a rat vitronectin sequence between residues 108-135. Following this domain is an RRKR motif, a putative cleavage site for intracellular activation by furin proteinases. XMMP lacks a proline-rich linker peptide, or hinge region, typically found in other MMPs between the catalytic domain and carboxyl-terminal "hemopexin/vitronectin-like" domain. In XMMP, the carboxyl-terminal domain is composed of four tandem repeats that are 21-33% identical to a sequence (residues 213-264) encoded by vitronectin exon-5. Interestingly, XMMP gene is transiently expressed during Xenopus embryo development. XMMP mRNA of 3.0 kilobase pairs was undetected in the blastula stage embryo, induced in gastrula embryo, expressed in neurula embryo, and then down-regulated in pretailbud embryo. In comparison, other Xenopus MMP genes that we have cloned show a different developmental regulation. In blastula embryo, the only MMP gene expressed was found to be 92-kDa type IV collagenase, which was also expressed in the gastrula, neurula, and pretailbud embryos. Expression of stromelysin-1, stromelysin-3, and two different membrane type-MMPs was first detected in the neurula and pretailbud embryos. These results suggest that MMPs and the novel XMMP reported here play a role in Xenopus early development.
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PMID:A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development. 915 98

N-terminal analysis of aggrecan fragments lost from bovine nasal cartilage cultured in the presence of recombinant human interleukin 1alpha revealed a predominant ARGSVIL sequence with an additional ADLEX sequence. Production of the ARGSVIL-containing fragments has been attributed to the action of a putative proteinase, aggrecanase. The minor sequence (ADLEX) corresponds to a new reported cleavage product; comparison of this sequence with the available partial sequence of bovine aggrecan indicates that this is the product of a cleavage occurring towards the C-terminus of the protein. Matrix metalloproteinase (MMP) inhibitors inhibited aggrecan loss from bovine nasal explants incubated in the presence of recombinant human interleukin 1alpha. A strong correlation between inhibition of aggrecan metabolism and inhibition of stromelysin 1 (MMP 3) (r=0.93) suggests a role for stromelysin or a stromelysin-like enzyme in cartilage aggrecan metabolism. However, the compounds were approx. 1/1000 as potent in inhibiting aggrecan loss from the cartilage explants as they were in inhibiting stromelysin. There was little or no correlation between inhibition of aggrecan metabolism and inhibition of gelatinase B (MMP 9) or inhibition of collagenase 1 (MMP 1). Studies with collagenase inhibitors with a range of potencies showed a correlation between inhibition of collagenase activity and inhibition of collagen degradation in the cartilage explant assay. This indicates that in interleukin 1alpha-driven bovine nasal cartilage destruction, stromelysin (or a closely related enzyme) is involved in aggrecan metabolism, whereas collagenase is principally responsible for collagen degradation.
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PMID:Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors. 916 42

We have developed a novel murine mammary tumor system with variants representing different stages of tumor progression. The MXT-s parental cell line was established from a urethane-induced and hormone-sensitive mammary tumor. MXT-s parental cells are highly tumorigenic but poorly metastatic. MXT clones and variants were selected by either in vitro or in vivo procedures, and they differ in metastatic ability and 17 beta-estradiol dependency for tumor growth. The MXT-c1.1 and MXT-B2 cell lines produced lung metastasis after intravenous injection into 100% of syngenic mice, but only MXT-c1.1 cells were highly metastatic from intramammary tumors. The fingerprints obtained by arbitrarily primed-polymerase chain reaction demonstrated that the metastatic variants and clones had a common genetic background and resulted from clonal selection from the parental cell line. We studied whether the matrix metalloproteinase (MMP) profile is correlated with tumor progression and metastatic ability in the MXT tumor system. Gelatinases A and B were assayed in the cells, both by enzyme activity and mRNA expression. Gelatinase A was expressed in MXT-c1.1 cells, whereas MXT-B2 cells did not express either MMP. In contrast, the mammary fat pad tumors expressed both gelatinases. Membrane Type 1-MMP transcripts were also detected in MXT cells and tumors. Because the mRNA levels of gelatinase. A were low in MXT-B2 tumors, we suggested that exogenous gelatinase A bound the cell membranes of MXT-B2 cells in vivo. Indirect evidence was obtained in vitro by treatment of MXT-B2 cells with NIH/3T3 fibroblast-conditioned medium. After this treatment, we detected a gelatinolytic activity at M(r) 68,000 in the cell-membrane extract of MXT-B2 cells and an increase in migratory ability through type IV collagen matrices. On the other hand, Ha-ras gene dosage correlated positively with metastatic ability but not with either gelatinase A or gelatinase B expression. No significant differences were observed in the expression of stromelysin-1 and tissue inhibitors of MMP. Thus, in the MXT tumor system, the expression of gelatinase A or its cell association and Ha-ras gene dosage independently contribute to the metastatic phenotype.
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PMID:Metastatic ability of MXT mouse mammary subpopulations correlates with clonal expression and/or membrane-association of gelatinase A. 918 Sep 29


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