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 wellestablished 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 ofwhich 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 sinficance, contributing to the destabilization of the extracellular matrix and eventual plaque rupture.The morphology of atheromatous plaques ranges from solid fibrous structures to those with a substantial lipid core, covered by a fibrous cap (1). Fibrous plaques are essentially stable lesions, but the "soft," lipid-laden plaques are prone to intimal tearing (fissuring), the commonest event initiating coronary thrombosis (2). Migration of macrophages and T cells into soft plaques has been observed, and the lesion has all the hallmarks of an inflammatory response (3). As macrophages produce a number of potent proteases (4), their presence in large numbers may lead to plaque rupture as a result of destabilization of the supporting connective tissue matrix. Alternatively, cytokines and growth factors secreted by activated macrophages (5) may induce neighboring cells, such as smooth muscle cells, to erode the collagen and elastin that forms the framework of the plaque.Stromelysins are a group of enzymes within the mammalian tissue metalloproteinase (MP) family. These proteinases are generally characterized by their ability to function at neutral pH, the need to bind Zn2+ as a cofactor, and their secretion in a latent form requiring activation for proteolytic activity (6, 7). As a group, the tissue MPs have the capacity to completely degrade all extracellular matrix macromolecules, playing a major role in both physiological and pathological events that lead to matrix degradation. Stromelysins are produced by a variety ofcell types, have a broad substrate specificity, and can degrade most of the constituents of the extracellular matrix within atherosclerotic plaques. Stromelysins 1 and 2 have an identical spectrum of activity (reviewed in refs. 6 and 8), but stromelysin 1 is more potent (9). The principal substrate is proteoglycan core protein, but these enzymes also degrade nonhelical regions of types II, IV,...
Concanavalin A-stimulated fibroblasts expressing MT1-MMP and fibroblast-derived plasma membranes were able to process human procollagenase-3 via a M r 56,000 intermediate form to the final M r 48,000 active enzyme which, by analogy with progelatinase A activation, may represent a model system for in vivo activation. Inhibition experiments using tissue inhibitor of metalloproteinases, plasminogen activator inhibitor-2, or aprotinin demonstrated that activation in the cellular model system was due to MT1-MMP/gelatinase A and excluded the participation of serine proteinases such as plasmin during procollagenase-3 activation. We have established that progelatinase A can considerably potentiate the activation rate of procollagenase-3 by crude plasma membrane preparations from concanavalin Astimulated fibroblasts, thus confirming our results using purified progelatinase A and MT1-MMP. This new activation cascade may be significant in human breast cancer pathology, where all three enzymes have been implicated as playing important roles.Degradation of the extracellular matrix during tumor invasion is thought to result from a combined action of several proteolytic enzyme systems, including the collagenases and other matrix metalloproteinases (MMPs) 1 (1, 2) and serine proteases, such as plasmin generated by the urokinase pathway of plasminogen activation (3).Human collagenase-3 (MMP-13), a new member of the MMP family, is expressed by breast tumors and is likely to play a crucial role in the modulation of extracellular matrix degradation and cell-matrix interactions involved in metastasis (4). Procollagenase-3 comprises three distinct domains which include an 85-amino acid residue propeptide that is lost during activation (5), and in which the conserved sequence PRCGVPD is responsible for the latency of the MMPs (6). This sequence is followed by the catalytic domain containing the active site of the enzyme linked via a short hinge sequence motif to the third, C-terminal domain, that shows homology to vitronectin and which is essential for the collagenolytic activity of collagenase-3.2 Collagenase-3 is a powerful collagenolytic and gelatinolytic enzyme that preferentially cleaves type II collagen, and it can therefore be implied that this enzyme may play a considerable role in connective tissue turnover (5). One of the key events in the regulation of extracellular collagenolytic activity is the activation of procollagenase-3, but there are currently only limited data available on how this may occur in vivo. We have recently shown that procollagenase-3 can be directly activated by stromelysin (5); however, other mechanisms may be of physiological and pathophysiological significance.Increasing evidence is accumulating that the newly discovered membrane associated MMPs (MT-MMPs) act as cell surface activator(s) of progelatinase A (proMMP-2) under physiological or pathophysiological conditions (7-12). This mechanism was thought to be specific for progelatinase A, since other MMPs such as progelatinase B, fibroblast procollage...
SW1353 chondrosarcoma cells cultured in the presence of interleukin-1, concanavalin A or PMA secreted procollagenase 3 (matrix metalloproteinase-13). The enzyme was detected in the culture medium by Western blotting using a specific polyclonal antibody raised against recombinant human procollagenase 3. Oncostatin M enhanced the interleukin-1-induced production of procollagenase 3, whereas interleukin-4 decreased procollagenase 3 synthesis. The enzyme was latent except when the cells had been treated with concanavalin A, when a processed form of 48 kDa, which corresponds to the active form, was found in the culture medium and collagenolytic activity was detected by degradation of 14C-labelled type I collagen. The concanavalin A-induced activation of procollagenase 3 coincided with the processing of progelatinase A (matrix metalloproteinase-2) by the cells, as measured by gelatin zymography. In addition, progelatinase B (matrix metalloproteinase-9) was activated when gelatinase A and collagenase 3 were in their active forms. Concanavalin A treatment of SW1353 cells increased the amount of membrane-type-1 matrix metalloproteinase protein in the cell membranes, suggesting that this membrane-bound enzyme participates in an activation cascade involving collagenase 3 and the gelatinases. This cascade was effectively inhibited by tissue inhibitors of metalloproteinases-2 and -3. Tissue inhibitor of metalloproteinases-1, which is a much weaker inhibitor of membrane-type 1 matrix metalloproteinase than tissue inhibitors of metalloproteinases-2 and -3 [Will, Atkinson, Butler, Smith and Murphy (1996) J. Biol. Chem. 271, 17119-17123], was a weaker inhibitor of the activation cascade.
Objective-To assess the likely importance of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the arthritic process. Methods-Synovial samples from seven joints with rheumatoid arthritis and three osteoarthritic joints were analysed by indirect immunofluorescence microscopy. Using specific human antisera, we documented the frequencies and distributions of collagenase, stromelysins 1 and 2, matrilysin, gelatinases A and B, TIMP-1, and TIMP-2.
Aims-To investigate the role of the matrix metalloproteinases (MMPs) in the connective tissue changes seen in the intestine in Crohn's disease. Methods-Indirect immunofluorescence microscopy using specific antibodies to the MMPs (collagenase, gelatinase A and B, and stromelysin) were used to assess the distribution of these enzymes in normal and diseased intestine. Results-In normal intestine the matrix metalloproteinases were confined to a few isolated inflammatory cells, but in Crohn's disease, the inflammatory infiltrate was associated with increased numbers of polymorphonuclear leucocytes which stained positive for gelatinase B. Stromelysin was also detected extracellularly on the connective tissue matrix in regions of smooth muscle cell proliferation and mucosal degradation. Interestingly, in ulcerative colitis, another inflammatory bowel disease, stromelysin was localised in the lamina propria in regions of mucosal loss. Conclusions-The increased numbers of inflammatory cells containing gelatinase B, and the localisation of extracellular stromelysin in regions of fibrosis and mucosal degradation, suggest that these enzymes have a role in the pathological changes seen in Crohn's disease. In cases of ulcerative colitis stromelysin was also detected on the laIina propria in regions of mucosal loss, and seems to be associated with the connective tissue changes that precede mucosal loss.
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