Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A small uterine metalloproteinase of the rat has been shown by amino acid and cDNA sequencing to be orthologous to human pump-1. Both proteinases are now designated as matrilysin or matrix metalloproteinase 7. The properties of purified uterine metalloproteinase and recombinant pump-1 were compared. Their specificities on substrates (gelatins, fibronectin, transferrin, elastin, Azocoll, and (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3,[2, 4-dinitrophenyl]-L-2, 3-diaminopropionyl)-Ala-Arg-NH2) are similar and distinct from those of the stromelysins and gelatinases. The two matrilysins have similar sensitivity to hydroxamate and pseudopeptide inhibitors. Rat matrilysin selectively cleaves the alpha 2(I) chain of rat gelatin, producing major cuts at Gly713-decreases-Ile714, Gly775-decreases-Leu776, and Gly809-decreases-Ile810. Rat matrilysin produces maximum activation of latent human interstitial collagenase 1 (pro-matrix metalloproteinase 1) when added in the presence of 4-aminophenylmercuric acetate (APMA) by cleaving the Gln80-decreases-Phe81 bond. Rat and human matrilysin do not directly activate latent rat collagenase 3 (matrix metalloproteinase 13) and do not enhance its activation when added together with APMA. Autoactivation of collagenase 3 in the presence of APMA results in cleavage at Val81-decreases-Tyr82 corresponding to the Gln80-decreases-Phe81 cleavage in collagenase 1. Thus collagenase 3 is capable of maximal autoactivation, whereas collagenase 1 is dependent upon another matrix metalloproteinase in order to be activated to its full potential.
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PMID:Characterization of rat uterine matrilysin and its cDNA. Relationship to human pump-1 and activation of procollagenases. 760 62

Degradation of the large cartilage proteoglycan aggrecan in arthritis involves an unidentified enzyme aggrecanase, and at least one of the matrix metalloproteinases. Proteinase-sensitive cleavage sites in the aggrecan interglobular domain (IGD) have been identified for many of the humman MMPs, as well as for aggrecanase and other proteinases. The major MMP expressed by chondrocytes stimulated with retinoic acid to degrade their matrix is collagenase-3 or MMP-13. Because of its potential role in aggrecan degradation we examined the specificity of MMP-13 for an aggrecan substrate. The results show that MMP-13 cleaves aggrecan in the IGD at the same site (..PEN314-FFG..) identified for other members of the MMP family, and also at a novel site ..VKP384-VFE.. not previously observed for other proteinases.
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PMID:Degradation of cartilage aggrecan by collagenase-3 (MMP-13). 860 31

Evidence indicates that matrix metalloproteinases (MMPs) are essentially involved in the postpartum involution of the uterus. As little information exists about the gene regulation of those MMPs in the uterus, this study aimed to characterize the time course of messenger RNA (mRNA) levels of rat collagenase (MMP-13) and matrilysin (MMP-7) in virgin, late pregnant (18th and 21st day), and postpartum rats (1, 2, 3, and 4 days postpartum). Rat collagenase (MMP-13) mRNA levels were very low in virgin and pregnant animals, but increased transiently 30-fold postpartum, reaching a maximum on the second day postpartum. The temporal course of mRNA levels of matrilysin (MMP-7) shows similarity with that of collagenase mRNA levels, but at any stage the abundance of matrilysin mRNA was at least 100-fold higher than that of collagenase. In virgin animals, matrilysin mRNA levels were dependent on the estrous cycle, being 3- to 4-fold higher in the estrous and diestrous stages than during metestrus. MMP-7 shows an approximately 25-fold induction when comparing the mRNA levels in late pregnancy and 2 days postpartum. In cervexes of virgin, pregnant, and postpartum groups, collagenase mRNA was not detectable. Matrilysin in cervix shows temporal mRNA expression similar to that in uterus, with a maximum on day 1 postpartum. In cervix, we found a 14-fold induction when comparing levels in late pregnancy and those 1 day postpartum. Taken together, our findings suggest that the increased activity of MMPs in the postpartum uterus is due to a strong increase in the mRNA levels of MMP-13 and MMP-7.
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PMID:Messenger ribonucleic acid levels of collagenase (MMP-13) and matrilysin (MMP-7) in virgin, pregnant, and postpartum uterus and cervix of rat. 894 Mar 67

Skin wound healing depends on cell migration and extracellular matrix remodeling. Both processes, which are necessary for reepithelization and restoration of the underlying connective tissue, are believed to involve the action of extracellular proteinases. We screened cDNA libraries and we found that six matrix metalloproteinase genes were highly expressed during rat skin wound healing. They were namely those of stromelysin 1, stromelysin 3, collagenase 3, gelatinase A (GelA), gelatinase B, and membrane type-1 matrix metalloproteinase (MT1-MMP). The expression kinetics of these MMP genes, the tissue distribution of their transcripts, the results of cotransfection experiments in COS-1 cells, and zymographic analyses performed using microdissected rat wound tissues support the possibility that during cutaneous wound healing pro-GelA and pro-gelatinase B are activated by MT1-MMP and stromelysin 1, respectively. Since MT1-MMP has been demonstrated to be a membrane-associated protein (Sato, H., T. Takino, Y. Okada, J. Cao, A. Shinagawa, E. Yamamoto, and M. Seiki. 1994. Nature (Lond.). 370: 61-65), our finding that GelA and MT1-MMP transcripts were expressed in stromal cells exhibiting a similar tissue distribution suggests that MT1-MMP activates pro-GelA at the stromal cell surface. This possibility is further supported by our observation that the processing of pro-GelA to its mature form correlated to the detection of MT1-MMP in cell membranes of rat fibroblasts expressing the MT1-MMP and GelA genes. These observations, together with the detection of high levels of the mature GelA form in the granulation tissue but not in the regenerating epidermis, suggest that MT1-MMP and GelA contribute to the restoration of connective tissue during rat skin wound healing.
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PMID:Expression of matrix metalloproteinases during rat skin wound healing: evidence that membrane type-1 matrix metalloproteinase is a stromal activator of pro-gelatinase A. 910 37

Collagenase-3 (MMP-13) is a recently identified member of the human matrix metalloproteinase gene family that is expressed in breast carcinomas and in articular cartilage from arthritic patients. Here, we have studied the cellular origin of this enzyme in breast carcinomas by in situ RNA hybridization, and we found that collagenase-3 is expressed by stromal cells immediately adjacent to epithelial tumor cells but not by the tumor cells themselves; nor is it expressed by the normal breast glandular epithelium. Consistent with this observation, coculture experiments using human fibroblasts and MCF-7 breast cancer cells revealed that conditioned medium from breast cancer cells stimulated the fibroblastic expression of collagenase-3 mRNA. In contrast, no stimulatory effect was observed when medium from fibroblast cells was added to breast cancer cells. These results strongly suggest that transcription of collagenase-3 in stromal cells is activated by diffusible factors released from epithelial breast cancer cells. A survey of a series of cytokines and growth factors known for their ability to induce collagenase-3 expression in human fibroblasts identified interleukin-1alpha and interleukin-1beta as potential candidates for inducing the expression of this MMP gene in breast carcinomas. According to these results, collagenase-3 should be included among the molecular factors that are detected during the stromal reaction to invasive breast cancer and that, by concerted action, may be essential for tumor growth and progression.
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PMID:Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal-epithelial cell interactions. 935 53

Programmed expression of matrix metalloproteinases is involved in wound healing in various organs. We have previously demonstrated enhanced expression of collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define the role of matrix-degrading enzymes and their inhibitors in intestinal inflammation and ulcerations, the expression of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3 mRNAs was studied using in situ hybridization and immunohistochemistry in 38 samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and normal intestine. As controls for normally healing intestinal wounds, 12 postoperative samples of rat experimental jejunal anastomoses were also examined. The colitis types studied did not essentially differ in their MMP expression. We found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes bordering the ulcerations. HME was abundantly expressed by macrophages in the vicinity of shedding mucosal epithelium and beneath the necrotic surface of the ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3 was observed in granulation tissue, but not the epithelium, of the rat anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration and for metalloelastase in macrophage movement and epithelial cell shedding.
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PMID:Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. 954 61

The mechanisms responsible for the induction of matrix-degrading proteases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of extracellular matrix at sites of inflammation. We find a localized increase in the expression of the rat interstitial collagenase (MMP-13; collagenase-3) gene from fibroblastic cells directly adjacent to macrophages within silicotic rat lung granulomas. Conditioned medium from macrophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medium from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene expression. Tumor necrosis factor-alpha (TNF-alpha) alone did not induce interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulation of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-alpha and 12-lipoxygenase-derived arachidonic acid metabolites. The fibroblast response to this conditioned medium was dependent on de novo protein synthesis and involved the induction of nuclear activator protein-1 activity. These data reveal a novel requirement for macrophage-derived 12-lipoxygenase metabolites in lung fibroblast MMP induction and provide a mechanism for the induction of resident cell MMP gene expression during inflammatory lung processes.
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PMID:Collagenase-3 induction in rat lung fibroblasts requires the combined effects of tumor necrosis factor-alpha and 12-lipoxygenase metabolites: a model of macrophage-induced, fibroblast-driven extracellular matrix remodeling during inflammatory lung injury. 961 83

Recently, we have shown that the tumor necrosis factor-alpha (TNF-alpha)-induced morphological change of EA.hy 926 human endothelial cells is associated with a decrease in the net synthesis of two proteoglycans (PGs), biglycan and syndecan-1, both of which have been suggested to play a role in cell adhesion. Here we have examined whether this phenotypic modulation of EA.hy 926 cells also involves altered expression of matrix metalloproteinases (MMPs) or their tissue inhibitors (TIMPs). We demonstrate that, when forming cobblestone-like monolayer cultures, these cells express and synthesize collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and 72 kDa (MMP-2) and 92 kDa (MMP-9) gelatinases, all of which have previously been found in either normal or pathological human vascular wall. EA.hy 926 cells also express membrane-typel MMP (MT1-MMP), but not matrilysin (MMP-7) and collagenase-3 (MMP-13). As regards TIMPs, we show that these cells express TIMP-1 and TIMP-2, but not TIMP-3 or TIMP-4. Exposure of the cells to TNF-alpha changed the cell morphology from a polygonal shape into a spindle shape and also increased the mRNA levels of MMP-1, MMP-3 and MMP-9, but slightly decreased the MMP-2 mRNA level. No change at the mRNA level of MT1-MMP was observed. Similarly to unstimulated cultures, no mRNA for MMP-7 or MMP-13 was detected in the TNF-alpha treated cultures. TNF-alpha had no effect on the TIMP-1 and TIMP-2 mRNA levels and did not induce TIMP-3 or TIMP-4 expression. Gelatin zymography and Western blot analysis revealed that the increase observed at the mRNA level of MMP-3 and MMP-9 was similar to that of their net protein level; furthermore, the active form of MMP-1 was induced. Our results indicate that the TNF-alpha-induced morphological change of EA.hy 926 cells is associated not only with specific changes in the expression of PGs by the cells, but also with specific changes in the expression of MMPs.
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PMID:Collagenase-1, stromelysin-1 and 92 kDa gelatinase are associated with tumor necrosis factor-alpha induced morphological change of human endothelial cells in vitro. 974 45

Type II pneumocytes are essential for repair of the injured alveolar epithelium. The effect of two MMP collagenases, MMP-1 and MMP-13 on alveolar epithelial repair was studied in vitro. The A549 alveolar epithelial cell line and primary rat alveolar epithelial cell cultures were used. Cell adhesion and cell migration were measured with and without exogenous MMP-1. Wound healing of a cell monolayer of rat alveolar epithelial cell after a mechanical injury was evaluated by time lapse video analysis. Cell adhesion on type I collagen, as well as cytoskeleton stiffness, was decreased in the presence of exogenous collagenases. A similar decrease was observed when cell adhesion was tested on collagen that was first incubated with MMP-1 (versus control on intact collagen). Cell migration on type I collagen was promoted by collagenases. Wound healing of an alveolar epithelial cell monolayer was enhanced in the presence of exogenous collagenases. Our results suggest that collagenases could modulate the repair process by decreasing cell adhesion and cell stiffness, and by increasing cell migration on type I collagen. Collagen degradation could modify cell adhesion sites and collagen degradation peptides could induce alveolar type II pneumocyte migration. New insights regarding alveolar epithelial cell migration are particularly relevant to investigate early events during alveolar epithelial repair following lung injury.
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PMID:Role of collagenase in mediating in vitro alveolar epithelial wound repair. 985 77

Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.
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PMID:Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. 989 Oct 15


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