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

Destructive joint changes in rheumatoid arthritis (RA) are thought to be mediated in part by the neutral proteinases collagenase and stromelysin. Collagenase messenger RNA (mRNA) has been previously localized to the synovial lining layer. In this study, synovial tissue from 8 patients with RA and 2 patients with osteoarthritis was examined for proteinase production by in situ hybridization. Stromelysin mRNA localized predominantly to the synovial lining layer cells. In serial sections, collagenase mRNA was shown to be localized to the same tissue areas as those producing stromelysin mRNA, and grain counts revealed a direct correlation between production of stromelysin mRNA and production of collagenase mRNA. All patients with RA were producing collagenase and stromelysin mRNA in detectable amounts. One of 2 osteoarthritis patients was producing these metalloproteinases, but in levels below those found in the RA patients. These data support the identity of the synovial lining cells as the major synovial cells producing collagenase and stromelysin in RA and provide new evidence for the coordinate production of collagenase and stromelysin in RA in vivo.
Arthritis Rheum 1991 Sep
PMID:In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. 165 7

The expression of messenger RNA encoding neutral metalloproteinases and the tissue inhibitor of metalloproteinases (TIMP) in human arthritic synovium was evaluated in situ, using RNA probes. Interstitial collagenase and stromelysin were expressed by synovial lining cells in patients with active rheumatoid arthritis (RA). Proteinase messenger RNA was found both in cells expressing mononuclear phagocyte antigens and in cells that were negative for the antigens. TIMP was also expressed predominantly along the synovial lining layer. In highly inflammatory RA, TIMP expression appeared less intense than that of the proteases. In osteoarthritic synovium, TIMP was expressed at easily detectable levels, whereas the expression of collagenase and stromelysin was less prominent. The balance between expression of the metalloproteinases and of the metalloproteinase inhibitor in synovium appears to be altered during inflammation. These results are consistent with the notion that synovium plays different roles in the cartilage damage of RA and of osteoarthritis.
Arthritis Rheum 1991 Sep
PMID:Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. 165 8

A continuous caseinolytic activity assay has been developed and characterized with trypsin, a serine protease, and transin, a metalloproteinase. Beta-casein labeled with both N-(7-dimethylamino-4-methylcoumarinyl)-maleimide (DACM) and fluorescein isothiocyanate (FITC) is used as the substrate in this assay. The effect of proteolysis of the substrate is a reduction of the intermolecular energy transfer from DACM to FITC. The caseinolytic activity is then monitored by the fluorescence increase. The activities of both proteases obey Michaelis-Menten kinetics with Km = 1.6 +/- 0.2 microM for trypsin and Km = 13.2 +/- 1.9 microM for transin. Protease concentrations as low as 10 ng/mL can be utilized. The pH dependence of the caseinolytic activity has been determined for both enzymes.
Anal Biochem 1991 Sep 02
PMID:A continuous fluorescent assay for measuring protease activity using natural protein substrate. 178 89

We have developed a procedure for the use of minislab gels to electrophoretically separate proteoglycans (PGs), large macromolecules with molecular masses greater than 2.5 million Da. Our procedure is a modification of the method of C.A. McDevitt and H. Muir (Anal. Biochem. 44, 612-622, 1971) for agarose/polyacrylamide, composite tube gels. These 1% agarose/1.2% acrylamide minigels are run at 35 mA for 75 min; bands are visualized by toluidine blue staining. The subtle size differences between the large aggregating PGs isolated from rat chondrosarcoma, bovine nasal septal cartilage, and adult bovine articular cartilage (which consists of two subpopulations) can be distinguished by their migration on these large pore gels. Chondroitin sulfate chains, added to all wells as a marker of constant mobility, ran immediately behind the dye front. The distance of migration into the gel of PGs incubated overnight with cathepsin B, carboxypeptidase A, papain, plasmin, elastase, or cathepsin G varied with the size of the cleavage products. We propose the use of this procedure for a convenient assessment of cartilage PGs and a rapid, reproducible assay for proteoglycanase activity.
Anal Biochem 1991 Sep 02
PMID:Agarose/polyacrylamide minislab gel electrophoresis of intact cartilage proteoglycans and their proteolytic degradation products. 178 94

The stromelysins are members of a family of extracellular matrix metalloproteinases. These enzymes may erode the connective tissue in atherosclerotic plaques, leading to fissuring and acute thrombotic events. Cell-specific stromelysin expression in human atherosclerotic plaques was studied by in situ hybridization and immunocytochemistry. Sections were taken from nine coronary arteries: eight with well-established plaques and one normal. Unambiguous signals were seen in five plaques, two were inconclusive, and the remaining sample was negative, as was the normal coronary artery. Stromelysin mRNA transcripts were localized to isolated individual cells, some of which were smooth muscle, in the plaque cap, intima, and adventitia, but not the media. Expression was also seen in large clusters of macrophages that contained intracellular lipid deposits. The isolated expression of stromelysin by smooth muscle cells may reflect local connective tissue remodeling associated with growth and the formation of the plaque, whereas the more extensive expression associated with macrophages may be of greater pathological significance, contributing to the destabilization of the extracellular matrix and eventual plaque rupture.
Proc Natl Acad Sci U S A 1991 Sep 15
PMID:Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. 189 64

In previous work, we found that nerve growth factor (NGF) induced expression of the mRNA transcript encoding the metalloproteinase transin/stromelysin in PC12 cells. Transin was found, moreover, to be a "late" gene product whose expression correlated with neurites extension. In this study, various aspects of the NGF intracellular signaling pathway in PC12 cells are investigated. We show that the protein kinase inhibitor staurosporine, but not various other kinase inhibitors, specifically blocked the NGF induction of transin. Preliminary characterization of this staurosporine-sensitive kinase suggest that it does not correspond to a tyrosine kinase, nor various serine kinases, and that it is involved both at the transcriptional and posttranscriptional levels of transin gene regulation. In contrast to these effects of staurosporine, various activators of protein kinases C and A augmented the NGF induction of transin. Similar effects of these kinase inhibitors and activators were also observed with the expression of various immediate-early genes that have been proposed to mediate the transcriptional effects of NGF, including c-fos and c-jun. These data suggest, therefore, that the NGF induction of transin mRNA expression involves multiple protein kinases acting at a number of postreceptor regulatory steps in the NGF signaling pathway.
J Cell Biol 1991 Sep
PMID:NGF-induction of the metalloproteinase-transin/stromelysin in PC12 cells: involvement of multiple protein kinases. 190 68

The expression of the metalloproteinase stromelysin correlates with the progression of chemically induced squamous cell carcinomas. We demonstrate that the expression of activated stromelysin in papilloma-derived cells enhances in vitro cell invasion. We also demonstrate that the Ha-ras oncogene induces the transcription of the stromelysin gene through an AP-1 dependent pathway. The hypothesis is that alterations in oncogenes and suppressor genes influence stromelysin expression and thus influence subsequent steps of tumor invasion and metastasis.
Am J Med Sci 1991 Sep
PMID:The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas. 192 26

Chondrocytes subjected to adverse culture conditions in vitro are stimulated to produce the eicosanoid prostaglandin E2 (PGE2) and the neutral metalloproteinase stromelysin (proteoglycanase). This indicates the potential role of the chondrocyte in cartilage degeneration in equine clinical joint disease and suggests a mechanism which may be involved in the potentiation of the effects of other inflammatory mediators. Therefore, adverse conditions within the joint, such as decreased pH in an inflammatory focus and decreased access of nutrients to deeper layers of cartilage, might contribute to the activation of chondrocytes which leads to cartilage degradation.
Equine Vet J 1991 Sep
PMID:Adverse conditions in vitro stimulate chondrocytes to produce prostaglandin E2 and stromelysin. 195 31

The differentiation of F9 and PSA-1 embryonal carcinoma cells to embryoid bodies composed of a mixture of parietal and visceral endoderm was accompanied by changes in their secretion of metalloproteinases. Differentiation was induced by retinoic acid and dibutyryl cyclic AMP (for F9 cells) or by removing cells from a substrate of feeder cells to alter cell-cell interaction and adhesion (for PSA-1 cells). The embryoid bodies attached to gelatin-coated dishes, and the parietal endoderm cells spread out over the matrix. The differentiated cells secreted specific gelatin- and casein-degrading proteinases, including enzymes that comigrated with proenzyme forms of collagenase and stromelysin. Total proteinase activity as well as specific collagenase activity increased with the time of differentiation. All of the gelatin- and casein-degrading proteinases detectable by substrate gel zymography were inhibited by inhibitors of metalloproteinases but not by inhibitors of serine or cysteine proteinases, indicating that they were metalloproteinases. Both cell lines showed increased collagenolytic activity, which was activated by treatment with plasmin. In addition, both cell lines showed increased secretion of specific metalloproteinase inhibitors, including tissue inhibitor of metalloproteinases, with differentiation. Analysis of mRNA from undifferentiated and differentiated F9 cells by RNA blot analysis or reverse transcription coupled with the polymerase chain reaction showed that increased expression of genes for collagenase, stromelysin and tissue inhibitor of metalloproteinases is associated with differentiation of these cells. These results suggest that the expression of extracellular matrix-degrading metalloproteinases and their inhibitors is developmentally regulated during the differentiation and spreading of the parietal endoderm.
Development 1990 Sep
PMID:Expression of extracellular matrix-degrading metalloproteinases and metalloproteinase inhibitors is developmentally regulated during endoderm differentiation of embryonal carcinoma cells. 208 60

Inactivation of the plasma serine-proteinase inhibitor alpha 1-antitrypsin (alpha 1-AT) by neutrophil metalloproteinases has been reported [Vissers, George, Bathurst, Brennan & Winterbourn (1987) Fed. Proc. Fed. Am. Soc. Exp. Biol. 46, 1390a; (1988) J. Clin. Invest. 82, 706-711; Desrochers & Weiss (1988) J. Clin. Invest. 81, 1646-1650]. To identify the enzyme responsible, supernatant from neutrophils stimulated with phorbol 12-myristate 13-acetate was subjected to preparative SDS/PAGE, both with and without activation of latent metalloproteinases with HgCl2. The lanes were subsequently sliced into pieces, the slices incubated with equimolar amounts of type I collagen and alpha 1-AT in the presence of HgCl2, and the reaction products separated by SDS/PAGE. With the latent supernatant, the characteristic collagen-cleavage products and cleaved alpha 1-AT were present in the same slices, corresponding to an Mr of 80,000-85,000. On treatment with HgCl2 both degradative activities underwent the same molecular-mass shift to a position corresponding to Mr 60,000-65,000. Western blots of neutrophil supernatants, using a polyclonal antibody to purified collagenase, showed Mr values of 83,000 for the latent enzyme and 63,000 for the HgCl2-activated enzyme. Neutrophil collagenase was purified to homogeneity and shown also to exist in a second latent form with Mr 70,000. When activated to the Mr-63,000 form by HgCl2 and incubated with equimolar amounts of collagen and alpha 1-AT, collagenase cleaved alpha 1-AT at almost twice the rate at which collagen was cleaved. alpha 1-AT cleavage was inhibited by 1,10-phenanthroline and by high concentrations of collagen. That the purified collagenase did not contain a contaminant proteinase such as stromelysin was indicated by inability of the preparation to cleave casein. Taken together these results lead us to conclude that neutrophil collagenase is capable of degrading alpha 1-AT. Neutrophil gelatinase also cleaved alpha 1-AT, but cleavage was slow when compared with its activity against gelatin.
Biochem J 1990 Sep 15
PMID:Human neutrophil collagenase cleaves alpha 1-antitrypsin. 217 52


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