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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a novel nonsteroidal anti-inflammatory drug, 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl)propionic acid (CN-100), on the biosynthesis of proteoglycans in chondrocytes of rat femoral head articular cartilage was studied. Sodium salicylate and hydrocortisone inhibited significantly the biosynthesis proteoglycans, but CN-100 did not affect the biosynthesis of glycosaminoglycan chains nor their sulfation. The effect of CN-100 on the interleukin 1-induced biosynthesis of prostaglandin E2 (PGE2) and tissue collagenase in rabbit and human rheumatoid synovial fibroblasts was also examined. CN-100 did not inhibited directly the collagenase production, but significantly prevent the biosynthesis of PGE2 known as an inflammatory mediator. The 50% inhibitory concentration (IC50) of CN-100 on PGE2 of rabbit and human fibroblasts were 3.8 x 10(-9) M and 2.4 x 10(-8) M, respectively; an inhibitory effect of CN-100 was equivalent to that of a control drug, hydrocortisone (2.0 x 10(-9) M and 1.7 x 10(-8) M, respectively). These results indicate that CN-100 is a potent anti-inflammatory drug without affecting the proteoglycan biosynthesis.
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PMID:Effect of a novel anti-inflammatory drug, 2-(10, 11-dihydro-10-oxo-dibenzo[b,f]-thiepin-2-yl)propionic acid (CN-100), on the proteoglycan biosynthesis in articular chondrocytes and prostaglandin E2 production in synovial fibroblasts. 217 61

Cervical ripening is reviewed from the viewpoint of mechanical properties, histological and biochemical structure of cervical tissue, and the role of hormones and other bioactive agents in the process. The uterine cervix begins abruptly with a 2-3 mm transition from the myometrium and is made of 80% type I collagen and 20% type III collagen fibers covalently cross linked, and glycosaminoglyucans covalently bound to protein cores. During pregnancy the collagen concentration is halved and its extractability increases due to changes in the proteoglycan composition, an increase in acidic relative to neutral proteins. These changes are responsible for the softening of the cervix (Goodell's sign) and the isthmus (Hegar's sign). Histologically the collagen fibers appear thinner and more spread out. Polymorphonuclear leukocytes and eosinophils may be involved in the softening process. Factors theorized or know to be involved in cervical ripening are progesterone, estradiol, prostaglandins (PGs), relaxin, and cytokines. Progesterone withdrawal has been shown in animal models. Estradiol either induces PG synthesis or sensitizes the cervix to locally produced PGs. PGE2 and PGF2alpha receptors have been found in cervical plasma membranes, have been isolated from tissue, their local synthesis can be manipulated, and their clinical use is well documented. Relaxin is a peptide synthesized in the corpus luteum, uterus and placenta, and is known to relax the pelvic girdle, restrain myometrial activity and soften the cervix. Cytokines such as interleukin-1 and tumor necrosis factor are being studies because of their ability to stimulate collagenase.
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PMID:The physiology of cervical ripening and cervical dilatation and the effect of abortifacient drugs. 222 99

Human rheumatoid synovial cells in culture secrete at least three related metalloproteinases that digest extracellular matrix macromolecules. One of them, termed matrix metalloproteinase 2 (MMP-2), has been purified as an inactive zymogen (proMMP-2). The final product is homogeneous on SDS/PAGE with Mr = 72,000 under reducing conditions. The NH2-terminal sequence of proMMP-2 is Ala-Pro-Ser-Pro-Ile-Ile-Lys-Phe-Pro-Gly-Asp-Val-Ala-Pro-Lys-Thr, which is identical to that of the so-called '72-kDa type IV collagenase/gelatinase'. The zymogen can be rapidly activated by 4-aminophenylmercuric acetate to an active form of MMP-2 with Mr = 67,000, and the new NH2-terminal generated is Tyr-Asn-Phe-Phe-Pro-Arg-Lys-Pro-Lys-Trp-Asp-Lys-Asn-Gln-Ile. However, following 4-aminophenylmercuric acetate activation, MMP-2 is gradually inactivated by autolysis. Nine endopeptidases (trypsin, chymotrypsin, plasmin, plasma kallikrein, thrombin, neutrophil elastase, cathepsin G, matrix metalloproteinase 3, and thermolysin) were tested for their abilities to activate proMMP-2, but none had this ability. This contrasts with the proteolytic activation of proMMP-1 (procollagenase) and proMMP-3 (prostromelysin). The optimal activity of MMP-2 against azocoll is around pH 8.5, but about 50% of activity is retained at pH 6.5. Enzymic activity is inhibited by EDTA, 1,10-phenanthroline or tissue inhibitor of metalloproteinases, but not by inhibitors of serine, cysteine or aspartic proteinases. MMP-2 digests gelatin, fibronectin, laminin, and collagen type V, and to a lesser extent type IV collagen, cartilage proteoglycan and elastin. Comparative studies on digestion of collagen types IV and V by MMP-2 and MMP-3 (stromelysin) indicate that MMP-3 degrades type IV collagen more readily than MMP-2, while MMP-2 digests type V collagen effectively. Biosynthetic studies of MMPs using cultured human rheumatoid synovial fibroblasts indicated that the production of both proMMP-1 and proMMP-3 is negligible but it is greatly enhanced by the treatment with rabbit-macrophage-conditioned medium, whereas the synthesis of proMMP-2 is constitutively expressed by these cells and is not significantly affected by the treatment. This suggests that the physiological and/or pathological role of MMP-2 and its site of action may be different from those of MMP-1 and MMP-3.
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PMID:Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. 226 96

Proteoglycans were extracted from nuclease-digested sonicates of 10(9) rat basophilic leukemia (RBL-1) cells by the addition of 0.1% Zwittergent 3-12 and 4 M guanidine hydrochloride and were purified by sequential CsCl density gradient ultracentrifugation, DE52 ion exchange chromatography, and Sepharose CL-6B gel filtration chromatography under dissociative conditions. Between 0.3 and 0.8 mg of purified proteoglycan was obtained from approximately 1 g initial dry weight of cells with a purification of 200-800-fold. The purified proteoglycans had a hydrodynamic size range of Mr 100,000-150,000 and were resistant to degradation by a molar excess of trypsin, alpha-chymotrypsin, Pronase, papain, chymopapain, collagenase, and elastase. Amino acid analysis of the peptide core revealed a preponderance of Gly (35.4%), Ser (22.5%), and Ala (9.5%). Approximately 70% of the glycosaminoglycan side chains of RBL-1 proteoglycans were digested by chondroitinase ABC and 27% were hydrolyzed by treatment with nitrous acid. Sephadex G-200 chromatography of glycosaminoglycans liberated from the intact molecule by beta-elimination demonstrated that both the nitrous acid-resistant (chondroitin sulfate) and the chondroitinase ABC-resistant (heparin/heparan sulfate) glycosaminoglycans were of approximately Mr 12,000. Analysis of the chondroitin sulfate disaccharides in different preparations by amino-cyano high performance liquid chromatography revealed that 9-29% were the unusual disulfated disaccharide chondroitin sulfate di-B (IdUA-2-SO4----GalNAc-4-SO4); the remainder were the monosulfated disaccharide GlcUA----GalNAc-4-SO4. Subpopulations of proteoglycans in one preparation were separated by anion exchange high performance liquid chromatography and were found to contain chondroitin sulfate glycosaminoglycans whose disulfated disaccharides ranged from 9-49%. However, no segregation of subpopulations without both chondroitin sulfate di-B and heparin/heparan sulfate glycosaminoglycans was achieved, suggesting that RBL-1 proteoglycans might be hybrids containing both classes of glycosaminoglycans. Sepharose CL-6B chromatography of RBL-1 proteoglycans digested with chondroitinase ABC revealed that less than 7% of the molecules in the digest chromatographed with the hydrodynamic size of undigested proteoglycans, suggesting that at most 7% of the proteoglycans lack chondroitin sulfate glycosaminoglycans.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purification and characterization of protease-resistant secretory granule proteoglycans containing chondroitin sulfate di-B and heparin-like glycosaminoglycans from rat basophilic leukemia cells. 241 30

Using a novel method, a monoclonal antibody was produced which can directly block the activity of an extracellular matrix-associated neurite outgrowth promoting complex (Matthew and Patterson, 1983). Presumably binding at or near the active site, this antibody recognizes a determinant consisting of heparan sulfate and a larger molecule which is likely to be laminin (Matthew et al., in preparation). The antibody has been further used to localize this determinant in adult tissues in vivo. Extracellular binding is seen at sites known to promote axon regeneration in the peripheral nervous system and is not seen in the central nervous system (Matthew et al., in preparation). In investigating how neurons may modify their environment as they grow processes, we have recently found that sensory and sympathetic neurons spontaneously release a collagenase and a plasminogen activator from their distal processes and/or growth cones (Pittman, 1985). A 43 kD irreversible inhibitor of the plasminogen activator is secreted by cardiac myocytes and is found on the surfaces of cultured neurons (Pittman, 1984). This inhibitor is also released by nonneuronal cell cultures from peripheral, but not central, nerves (Pittman, unpublished). Of interest in relation to the proteoglycan neurite outgrowth promoting complex is the finding that the 43 kD inhibitor preparation binds heparin tightly and can displace laminin from its heparin binding site (Patterson and Pittman, unpublished). Thus it is possible that the protease/inhibitor system could affect outgrowth via interaction with the neurite outgrowth promoting complex in the extracellular matrix.
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PMID:On the role of proteases, their inhibitors and the extracellular matrix in promoting neurite outgrowth. 242 54

Elastin was isolated from the human aorta by three different extraction methods. Immunization was carried out in sheep. The presence of antibody against each elastin preparation in the sheep sera was confirmed by immunofluorescence. However, antiserum against elastin isolated by collagenase/guanidine dithioerythritol showed the most specific reactions in the cryostat sections. No cross-reactivity to type I, III and IV collagen, fibronectin, laminin and proteoglycan BM 1 was observed.
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PMID:Preparation of a specific antiserum against elastin of the human aorta. 242 14

A metalloproteinase similar or identical to stromelysin was shown to co-purify with interstitial collagenase from the rat mammary carcinoma cell line, BC1. The mixture of BC1 metalloproteinase and collagenase degraded casein, gelatin, fibronectin, fibrinogen, laminin, proteoglycan and type IV collagen, in addition to types I and II collagen. Using SDS-PAGE and zymography, the Mr of both enzymes was 51.10(3). During storage, the 51.10(3) protein converted to fragments of Mr 34.10(3) and 24.10(3), and isoelectric points of 4.6-5.3 and 5.7-6.0, respectively. The fragments were separated from the intact (Mr 51.10(3) enzymes by DEAE-Sepharose chromatography, but intact metalloproteinase and collagenase activities resisted separation by a range of chromatographic methods. The Mr 34.10(3) fragment retained the proteinolytic activities of the intact enzymes, excepting collagenase cleavage of collagen types I and II. The Mr 24.10(3) fragment had no proteinolytic activity, showed an increase in Mr of 6.10(3) upon reduction, in common with the intact enzymes, and also had similar chromatographic properties to the intact enzymes. The data presented are consistent with a pattern of breakdown which is common to both collagenase and the metalloproteinase, and suggest that both enzymes are comprised of two protein domains.
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PMID:Identification of a metalloproteinase co-purifying with rat tumour collagenase and the characteristics of fragments of both enzymes. 253 40

The prophylactic effect of glycosaminoglycan polysulfuric acid ester (GAGPS) on cartilage lesions was studied using the Pond-Nuki model of canine osteoarthritis. Starting 2 days after anterior cruciate transection, GAGPS or saline was administered intraarticularly twice weekly for 4 weeks. After 4 weeks, gross and histologic medial femoral condylar lesions had developed to a lesser degree in GAGPS-treated dogs than in saline-treated dogs. The uronic acid and hydroxyproline levels in cartilage were significantly higher in the GAGPS-treated dogs than in the saline-treated dogs. Levels of active and latent collagenase in the cartilage of GAGPS-treated dogs were lower than in the cartilage of saline-treated dogs. With GAGPS treatment, swelling of the cartilage, an indicator of collagen network integrity, remained near control levels. Although increased synthesis of proteoglycan and collagen may account for some of these results, we propose that one mechanism of action of GAGPS is its ability to decrease collagen degradation, either by decreasing the synthesis of collagenase or by directly inhibiting the production of collagenase in cartilage.
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PMID:Prophylactic treatment of canine osteoarthritis with glycosaminoglycan polysulfuric acid ester. 254 87

A bovine articular cartilage longterm culture system was used to study proteoglycan synthesis by a pulse labeling technique. A brief preincubation of the cartilage slices with bacterial collagenase was found to be an effective method of depleting proteoglycan. The addition of a fraction from bovine bone that contained partially purified "matrigenin" activity to the cultures resulted in the stimulation of incorporation of radioactive precursors into cartilage chondroitin sulfate, suggesting increased proteoglycan synthesis. The stimulatory effect of matrigenin activity was observed earlier and was more sustained if the cartilage slices were preincubated with collagenase. The system appears to be useful for testing the hypothesis that bone derived factors stimulate the repair of damaged cartilage.
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PMID:The effects of "matrigenin" activity from bovine bone on the glycosaminoglycans of bovine articular cartilage in culture. A model for cartilage repair by bone derived factors. 254 77

Phospholipase A2 (PLA2) activity was measured in articular cartilage from normal and osteoarthritic (OA) human femoral heads. Protoglycanase and collagenase activity was determined in the same specimens using radiolabelled human proteoglycan subunit and type II collagen, respectively. Grossly normal and fibrillated OA cartilage samples showed a significant increase in PLA2 activity which was not found in osteophytic cartilage. PLA2 activity was found to be correlated with proteoglycanase but unrelated to collagenase activity. Tiaprofenic acid induced in vitro a concomitant increase in PLA2 and a decrease in proteoglycanase activity. PLA2 which may be activated by cytokines as well as mechanical factors is suggested as a key enzyme in chondrocyte metabolism regulation. Tiaprofenic acid is shown as a potential chondroprotective nonsteroidal anti-inflammatory drug.
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PMID:Phospholipase A2 activity in human osteoarthritic cartilage. 234 43


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