Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The effects of the chondroprotective drugs, sodium pentosan polysulphate (SP54) and Arteparon (glycosaminoglycan polysulphate), on the in vitro activities of the purified matrix metalloproteinases interstitial collagenase (matrix metalloproteinase 1, MMP1) and stromelysin (MMP3) were examined. Both drugs produced concentration-dependent enhancement of the degradation of type I collagen fibrils by purified human fibroblast collagenase and rat tumour collagenase. Rat collagenase activity was increased by drug concentrations above 0.5 microgram/mL, whereas human collagenase activity was only increased by higher drug concentrations, above 5 micrograms/mL. The concentration dependence of the increase in rat collagenase activity was similar for both drugs, with a maximal 3-fold increase at 50 micrograms/mL. In contrast, human collagenase activity was increased to a greater extent by SP 54 compared to Arteparon, with maximal increases at 5000 micrograms/mL of 6-fold and 2-4-fold, respectively. Both drugs produced concentration-dependent inhibition of the proteoglycan-degrading activity of both human fibroblast stromelysin and rat tumour stromelysin. Rat and human stromelysin activities were inhibited at drug concentrations above 0.005 microgram/mL, with a similar concentration dependence for both drugs. Fifty percent inhibition of rat stromelysin was produced by concentrations of each drug in the 0.5-5 microgram/mL range. The pattern of inhibition of human stromelysin was similar, except that drug concentrations in the 500-5000 micrograms/mL range produced 50% inhibition. The possible modes of action for these drug effects and their possible pharmacological significance are discussed.
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PMID:The chondroprotective drugs, Arteparon and sodium pentosan polysulphate, increase collagenase activity and inhibit stromelysin activity in vitro. 138 3

The mechanism of joint destruction in rapidly destructive coxopathy was studied by analyzing bone resorptive factors in the joint fluid. Prostaglandins were found to play a partial role in joint destruction. Some cases of rapidly destructive coxopathy revealed elevated levels of interleukin-1 beta (IL-1 beta) in the joint fluid. Electrophoretic analysis of proteolytic enzymes in polyacrylamide gel containing sodium dodecyl sulfate and copolymerized gelatin demonstrated that the resorptively active peptides have relative molecular weights (M(r)) of approximately 92,000, 72,000, and lower than 60,000. Cultured cells from synovia obtained perioperatively secreted matrix metalloproteinase 2 (MMP-2) with an M(r) of 72,000 and matrix metalloproteinase 3(MMP-3) with an M(r) of 57,000. Synovial cells from the patients with coxarthrosis secreted fewer proteolytic enzymes. Prostaglandins, IL-1 beta, MMP-2, and MMP-3 could act synergetically as promotors in the rapid destruction of the hip joint.
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PMID:Rapidly destructive arthropathy of the hip. Studies on bone resorptive factors in joint fluid with a theory of pathogenesis. 139 5

The effect of exogenous hyaluronate on normal cartilage metabolism and interleukin-1 (IL-1)-induced cartilage matrix degradation was investigated in a bovine cartilage explant culture system. Addition of hyaluronate at a concentration of 1.5 mg/ml to cartilage culture explants consistently decreased normal proteoglycan release from the matrix to a value less than that found in control cultures. Addition of 1.5 mg of hyaluronate/ml to IL-1 stimulated cartilage culture systems reduced proteoglycan release from the matrix by 83 to 113%. The reduction in control and IL-1-stimulated proteoglycan degradation by hyaluronate had a concentration-dependent trend. Evaluation of alterations in protein (enzyme) release by IL-1-stimulated chondrocytes after introduction of hyaluronate was evaluated by use of sodium dodecyl sulfate agar gel electrophoresis of cartilage-conditioned media. The quantity or the molecular weight profile of IL-1-induced proteins did not differ after introduction of hyaluronate into the culture system. Results indicate that introduction of high molecular weight hyaluronate into cartilage culture systems results in a decrease in proteoglycan release from the matrix in control systems, as well as in cultures incubated with IL-1. Because IL-1-stimulated protein synthesis by chondrocytes remains unchanged after addition of exogenous hyaluronate, the mechanism of inhibition of matrix degradation does not appear to be interference with binding of IL-1 to chondrocytes or to be inhibition of the production of neutral metalloproteases, including stromelysin.
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PMID:Inhibition of interleukin 1-mediated proteoglycan degradation in bovine articular cartilage explants by addition of sodium hyaluronate. 146 88

The effects of several nonsteroidal antiinflammatory drugs, used at concentrations achievable in synovial fluid, on human osteoarthritic (OA) cartilage metallo-protease activity in vitro was studied. Acetaminophen and ketoprofen had no effect; sodium salicylate, indomethacin, and diclofenac slightly decreased proteoglycanase activity. Piroxicam and tenoxicam suppressed proteoglycanase activity by 48.2% and 68.3%, respectively, and suppressed collagenase activity by 19.1% and 36.8%, respectively. Use of these NSAIDs may help to decrease cartilage catabolism in patients with OA.
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PMID:In vitro effect of nonsteroidal antiinflammatory drugs on proteoglycanase and collagenase activity in human osteoarthritic cartilage. 165 6

Substrate specificity studies of collagenase extracted from human rheumatoid synovium suggest that synovial pannus tissue overlying articular cartilage may not be particularly active in degradation of cartilage type II collagen, which, considering the poor inherent healing capacity of the articular hyaline cartilage, may exert a protective function against inadvertant tissue damage. Rheumatoid synovial tissue was also used to establish synovial fibroblast cell lines. Treatment of these cells in monolayer cultures with IL-1 leads to collagenase gene activation, increased collagenase production and an almost complete autoactivation of secreted collagenase. Interleukin-1 also activated stromelysin gene suggesting this as a possible mechanism effecting autoactivation. Latent human fibroblast and macrophage collagenase purified from culture medium were efficiently activated by phenylmercuric chloride but also by gold thioglucose, gold sodium thiomalate and HCIO. These new observations support the Cys73 switch activation mechanism. In contrast to neutrophil collagenase, the activation by gold(I) compounds and HCIO was associated with a change in the apparent molecular weight of the fibroblast procollagenase. In addition, gold(I) compounds rendered collagenase more susceptible to thermal denaturation. Thus the fibroblast-type interstitial collagenase, probably derived from fibroblast- and macrophage-like synoviocytes, seems to provide the predominant collagenolytic potential in human rheumatoid synovial tissue. Furthermore, the conditions in synovitis tissue may be such as to favor at least initial activation of collagenase synthesized and secreted in situ.
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PMID:Substrate specificity and activation mechanisms of collagenase from human rheumatoid synovium. 166 9

Extracellular matrix (ECM) turnover and remodeling are initiated, at least in part, by the regulated secretion of members of a family of matrix metalloproteinases. Human and bovine trabecular mesh-work in culture secrete interstitial collagenase, both the 72- and the 92-kD forms of type IV collagenase (gelatinases) and stromelysin, and the tissue inhibitor of metalloproteinases (TIMP). These proteinases and TIMP were identified by immunoblotting western transfers from sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) using several specific antiprotein and antipeptide polyclonal antibodies. Gelatinase and stromelysin enzymatic activities were also analyzed by substrate SDS-PAGE, in which proteinase substrates were polymerized into the gels before electrophoresis to allow subsequent activity assays. These matrix metalloproteinases and TIMP are secreted at low basal levels into trabecular culture medium; their secretion levels are increased several-fold by treatment of the cultures with the phorbol mitogen. 12-O-tetradecanoylphorbol-13-acetate (TPA). Characteristics of the trabecular matrix metalloproteinases and TIMP are similar to those secreted by numerous other tissues, including the retinal pigment epithelium. These proteinases may serve an important role in the maintenance and regulation of the trabecular extracellular matrix and, subsequently, of the aqueous humor outflow pathway in normal and glaucomatous eyes.
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PMID:Expression of matrix metalloproteinases and inhibitor by human trabecular meshwork. 184 30

We sought evidence of cytokine presence and interleukin-1 beta (IL-1 beta) bioactivity in 104 aerobic culture negative cyst fluids (CFs) from 13 kidneys of 13 patients with symptomatic normal to end-stage autosomal dominant polycystic kidney disease (ADPKD). ELISAs were used to detect IL-1 beta, interleukin-2 (IL-2), tumor necrosis factor alpha (TNF alpha) and stromelysin. Prostaglandin E2 (PGE2) was detected by radioimmunoassay. IL-1 beta was present in 65 of 94 (less than 20 to 419 pg/ml, TNF alpha in 54 of 75 (less than 10 to 73 pg/ml), stromelysin in 18 of 23 (less than 1.0 to 56 ng/ml), IL-2 in 7 of 23 (0.1 to 1.3 ng/ml) and PGE2 in 9 of 10 fluids (0.03 to 0.49 ng/ml). Of 51 fluids with immunoreactive IL-1 beta, 36 were mitogenic for thymocytes. IL-1 beta concentrations correlated directly with those of IL-2; IL-1 beta presence was associated with higher stimulation indices, higher mean concentrations of TNF alpha, IL-2, stromelysin, and PGE2, and with positive endotoxin assays, suggesting activation of the cytokine cascade in vivo. Cytokine, stromelysin and PGE2 concentrations did not correlate with sodium or non-sodium solute concentrations, nor with CF blood, osmolality, or endotoxin activity, indicating that differences in concentrations among fluids could not be explained by differences in water content. These data identify cytokines as candidate contributors to the morbidity and pathogenesis of ADPKD.
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PMID:Cytokines in fluids from polycystic kidneys. 205 29

The in vitro collagenolytic and proteoglycanasic activity from human fibrillated osteoarthritic cartilage was determined using labelled proteoglycans and type II collagen as substrates. In vitro, a glycosaminoglycan-peptide complex (GP-C Rumalon) induced a dose-dependent inhibition of both collagenolytic and proteoglycanasic activities while sodium salicylate and indomethacin had only a weak suppressive effect on proteoglycanase. Phospholipase A2 activity was unmodified by GP-C suggesting that the effect of the drug on degradative enzymes was unrelated to prostaglandin formation.
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PMID:Study of the effect of a glycosaminoglycan-peptide complex on the degradative enzyme activities in human osteoarthritic cartilage. 226 38

Connective tissue matrix-degrading metalloproteinases play an important role in cancer invasion. In this report we describe the isolation of a metalloproteinase exhibiting both type IV collagenolytic and gelatinolytic activities from the conditioned medium of NIH-3T3 fibroblasts transformed with DNA containing an activated c-Harvey-ras oncogene from T24 bladder cancer cells. This tumor proteinase was purified by anion exchange chromatography, zinc-chelate Sepharose chromatography, and gel permeation chromatography. The final product was homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (relative molecular mass = 67,000). Gelatin zymography revealed two bands of gelatinolytic activity, corresponding to molecular weights of 67,000 and 62,000. Upon immunoblotting with the use of an affinity-purified polyclonal rabbit antibody to a peptide region of type IV collagenase that lacks homology with interstitial collagenase or stromelysin, the purified tumor enzyme was identified as type IV collagenase.
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PMID:Purification of a gelatin-degrading type IV collagenase secreted by ras oncogene-transformed fibroblasts. 284 10

Culture medium from rabbit uterine cervical fibroblasts contained a procollagenase and a neutral proproteinase which acts as a procollagenase activator. These two proenzymes have been purified by a combination of ion-exchange, affinity and gel chromatographies. The purified neutral proproteinase showed Mr 60,000 with sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. This neutral proproteinase was activated by trypsin, 4-aminophenylmercuric acetate (APMA) and plasmin, and the active species of the proteinase had Mr 53,000 when activated by APMA; kallikrein and urokinase did not activate this proproteinase. The purified neutral proteinase was inhibited by EDTA, 1,10-phenanthroline and rabbit plasma, but not by serine proteinase inhibitors, suggesting that this proteinase is a metal-dependent proteinase. The purified enzyme could also degrade gelatin, casein, proteoglycan and type IV procollagen. The purified procollagenase had Mr 55,000 and was activated by trypsin, APMA and the active neutral proteinase. These activations were accompanied by decrease in Mr, and the activated species had an Mr which was approx. 10,000 less than that of the procollagenase. In particular, procollagenase activation with neutral proteinase depended on incubation time and proteolytic activity of proteinase. These results indicate that activation of procollagenase by the rabbit uterine neutral proteinase is related to limited proteolysis in the procollagenase molecule.
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PMID:Procollagenase activator produced by rabbit uterine cervical fibroblasts. 303 65


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