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)

The mechanism of proteoglycan (GAG) loss from rat femoral articular cartilage (FHC) induced by recombinant human interleukin-1 beta (rhIL-1 beta) in vitro has been investigated. The metalloproteinase inhibitor 1,10-phenanthroline, the serine proteinase inhibitor N alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK), the activator of latent metalloproteinase p-aminophenylmercuric acid (APMA), and an inhibitory metalloproteinase substrate analogue U27391 were tested for their ability to modulate rhIL-1 beta-induced GAG loss and GAG synthesis ([35S]O4 uptake) inhibition. As expected 1,10-phenanthroline inhibited GAG loss, however [35S]O4 incorporation was significantly reduced. TLCK was without effect, and APMA inhibited both parameters. U27391 reversed both the inhibition of [35S]O4 incorporation and GAG loss. It is concluded that the adverse effects on proteoglycan metabolism explain the inhibitory actions of 1,10-phenanthroline and APMA, whilst the action of TLCK may indicate that serine proteinases are not involved in the activation of latent metalloproteinase. U27391 exhibited chondroprotective activity and confirmed the induction of either metalloproteinases such as stromelysin or collagenase by rhIL-1 beta.
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PMID:Investigation of the role of metalloproteinases in recombinant human interleukin-1 beta-induced degradation of rat femoral head cartilage. 179 2

Recombinant human tissue inhibitor of metalloproteinase (rhTIMP) suppressed the ability of native human stromelysin to degrade [3H]transferrin in vitro. Maximum inhibition occurred at molar ratios (TIMP: stromelysin) of 2:1 and 1:1. Reduced and alkylated tissue inhibitor of metalloproteinases (TIMP) lost its ability to suppress stromelysin activity. rhTIMP also inhibited stromelysin from degrading proteoglycan monomer in vitro. When injected into the rat pleural cavity prior to stromelysin, rhTIMP inhibited the ability of the enzyme to degrade aggregating cartilage proteoglycan monomer. Marked inhibition of stromelysin-mediated proteoglycan degradation in vivo occurred at molar ratios (TIMP: enzyme) of 2:1 and 1:1, with less inhibition at molar ratios of 0.5:1 and 0.25:1. Reduction and alkylation prevented rhTIMP from suppressing stromelysin-mediated degradation of proteoglycan monomer in vivo. By comparison, an equimolar concentration of the serine proteinase inhibitor, alpha 1-proteinase inhibitor (alpha 1-PI), did not inhibit stromelysin activity in the rat pleural cavity. This study demonstrates that rhTIMP is effective in inhibiting native human stromelysin both in vitro and in vivo.
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PMID:In vivo activity of human recombinant tissue inhibitor of metalloproteinases (TIMP). Activity against human stromelysin in vitro and in the rat pleural cavity. 235 43

To elucidate structure-function relationships of stromelysin-3, a putative matrix metalloproteinase originally identified at the tumor-stromal cell interface in breast carcinomas, the human cDNA was expressed in mammalian cells, and its products were isolated and characterized. In stably transfected cells, stromelysin-3 was recovered as a complex mixture of species ranging in size from approximately 20 to 65 kDa. Among these products, a major 45-kDa species with an N terminus of Phe98 and an intact C-terminal domain was identified as a true endopeptidase on the basis of its ability to cleave the bait region of alpha 2-macroglobulin between Phe684 and Tyr685, a site identical to that recognized by stromelysin-1. However, unlike stromelysin-1 or other members of the matrix metalloproteinase family, the mature form of stromelysin-3 was unable to hydrolyze a range of extracellular matrix molecules associated with either the basement membrane or interstitium. To probe for alternate substrates among tumor cell-derived products, purified stromelysin-3 was incubated with [35S]methionine-labeled medium conditioned by the breast cancer cell line, MCF-7. Under these conditions, a single, tumor cell-derived protein was hydrolyzed as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Following anion-exchange chromatography and preparative gel electrophoresis, the stromelysin-3 substrate was identified by N-terminal sequencing as the serine proteinase inhibitor, alpha 1-proteinase inhibitor. Further studies demonstrated that stromelysin-3 rapidly destroyed the antiproteolytic function of alpha 1-proteinase inhibitor by cleaving the antiproteinase at a distinct site between Ala350 and Met351 within the reactive-site loop. Together, these data not only demonstrate that human stromelysin-3 acts as a powerful endopeptidase with a restricted substrate specificity distinct from all other matrix metalloproteinases, but also serve to identify serine proteinase inhibitors as potential physiologic targets at sites of extracellular matrix remodeling.
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PMID:Hydrolytic inactivation of a breast carcinoma cell-derived serpin by human stromelysin-3. 752 94

Along with degradation of type IV collagen in basement membrane, destruction of the stromal collagens, types I and III, is an essential step in the invasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)). Because A2058 melanoma cells produce substantial quantities of MMP-1, we used these cells as models for studying invasion of type I collagen. With a sensitive and quantitative in vitro invasion assay, we monitored the ability of these cells to invade a matrix of type I collagen and the ability of a serine proteinase inhibitor and all-trans-retinoic acid to block invasion. Although these cells produce copious amounts of MMP-1, they do not invade collagen unless they are co-cultured with fibroblasts or with conditioned medium derived from fibroblasts. Our studies indicate that a proteolytic cascade that depends on stromal/tumor cell interactions facilitates the ability of A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, particularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10(-6) M) suppresses the invasion of tumor cells by several mechanisms that include suppression of MMP synthesis and an increase in levels of tissue inhibitor of metalloproteinases 1 and 2. We conclude that invasion of stromal collagen by A2058 melanoma cells is mediated by a novel host/tumor cell interaction in which a proteolytic cascade culminates in the activation of pro-MMP-1 and tumor cell invasion.
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PMID:A novel host/tumor cell interaction activates matrix metalloproteinase 1 and mediates invasion through type I collagen. 1046 64

High blood flow causes intimal atrophy and loss of extracellular matrix in PTFE aortoiliac grafts. We have investigated whether matrix-degrading proteinases are altered in this baboon model of atrophy using zymography, western analysis, and a versican degradation assay. After four days of high flow, urokinase was increased and plasminogen activator inhibitor-1 was decreased in the intima. Plasminogen was increased after seven days. Pro-matrix metalloproteinase (MMP)-2, activated MMP-2, and proMMP-9 levels were modestly increased by high flow at 7 days, whereas MMP-3 and tissue inhibitor of metalloproteinases-1 were not altered. Extracts of 4-day high-flow intimas degraded more 35S-methionine-labeled versican than low-flow intimal extracts, and this activity was inhibited by AEBSF, a serine proteinase inhibitor, and a plasmin antibody. In contrast, this activity was not inhibited by the MMP inhibitor, BB-94 (Batimastat). These data suggest that serine proteinases, including plasmin, may be largely responsible for extracellular matrix degradation in this primate model of flow-induced intimal atrophy.
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PMID:Increased plasmin and serine proteinase activity during flow-induced intimal atrophy in baboon PTFE grafts. 1188 81