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)

Individual prostanoids have distinct potencies in activating intracellular signaling pathways and regulating gene expression in osteoblastic cells. The E-series prostaglandins (PGs) are known to stimulate matrix metalloproteinase-1 (MMP-1) synthesis and secretion in certain rodent and human osteoblastic cells, yet the intracellular events involved remain unclear. To further characterize this response and its signal transduction pathway(s), we examined prostanoid-induced expression of the MMP-1 gene in the rat osteoblastic osteosarcoma cell line UMR 106-01. Northern blot analysis demonstrated that prostaglandin E2 (PGE2) and PGE1 were very potent stimulators (40-fold) of MMP-1 transcript abundance, PGF2 alpha and prostacyclin were weak stimulators (4-fold), and thromboxane-B2 had no effect. The marked increase in MMP-1 transcript abundance after PGE2 treatment was first detected at 2 h, became maximal at 4 h, and persisted beyond 24 h. This response was dose dependent and elicited maximal and half-maximal effects with concentrations of 10(-6) and 0.6 x 10(-7) M, respectively. Cycloheximide, a protein synthesis inhibitor, completely blocked this effect of PGE2, suggesting that the expression of other genes is required. Nuclear run-on experiments demonstrated that PGE2 rapidly activates MMP-1 gene transcription, with a maximal increase at 2-4 h. The second messenger analog, 8-bromo-cAMP, mimicked the effects of PGE2 by stimulating a dose-dependent increase in MMP-1 messenger RNA (mRNA) levels, with a maximal effect quantitatively similar to that observed with PGE2. Thus, in UMR 106-01 cells, different prostanoids have distinct potencies in stimulating MMP-1 mRNA abundance. Our data suggest that PGE2 stimulation of MMP-1 synthesis is due to activation of MMP-1 gene transcription and a subsequent marked increase in MMP-1 mRNA abundance. This effect is dependent on de novo protein synthesis and is mimicked by protein kinase-A activation.
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PMID:Prostanoid-induced expression of matrix metalloproteinase-1 messenger ribonucleic acid in rat osteosarcoma cells. 792 6

Prostaglandins (PGs) may stimulate or inhibit bone cell replication and protein synthesis. These disparities may be concentration or time dependent, or occur in discrete cell types or by different second signals. Cell populations that express progressive degrees of osteoblast-like activity can be obtained by serial collagenase digestion of fetal rat parietal bone. The first (population 1) appears less differentiated, whereas the later (populations 3-5) exhibit biochemical features characteristic of osteoblasts. Within 24 h of treatment, three separate PGs increased DNA synthesis in population 1 with relative potencies of PGE1 < PGE2 < PGF2 alpha. By contrast, PGE1 and PGE2 (both strong cAMP inducers) inhibited basal DNA synthesis in population 3-5. These differences were paralleled by analogous changes in collagen and noncollagen synthesis in each population. The mitogenic effect in population 1 persisted for 72 h, and at later times was sensitive to indomethacin. These changes were unlikely to be cAMP dependent, as PGF2 alpha did not induce cAMP production, and the cAMP inducer forskolin was inhibitory. Moreover, phorbol ester treatment enhanced DNA synthesis to a greater extent in population 1 than in populations 3-5, and cotreatment with H-8 (at Km, approximately 10 microM) and staurosporine (at Km, approximately 0.01 microM) decreased the mitogenic effect of PGs in population 1, consistent with a reduction in protein kinase-C activation. These studies suggest that PGs activate less differentiated bone cells by a protein kinase-dependent event, whereas cAMP (induced by PGE1 and PGE2) decreases DNA and protein synthesis in more differentiated bone cells and tempers the increase in cellular activation found in population 1. Consequently, agents or events that increase the synthesis of specific PGs could differentially regulate, in positive and negative ways, biochemical activities in discrete bone cell populations.
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PMID:Differential actions of prostaglandins in separate cell populations from fetal rat bone. 792 24

The aim of the study was to investigate the effect of aging on cytoprotective properties of prostaglandins. Hepatocytes were obtained by collagenase perfusion of livers of young (4-6 mo) and old (24-28 mo) male Wistar rats. Cells were incubated for 1.5 h in Krebs-Ringer-bicarbonate buffer containing glucose and 3H-leucine in the presence of galactosamine (2.5-100 mM), PGE1, or two prostacyclin analogues: 9 beta-methylcarbacyclin and TRK-100. Cell damage was assessed by decrease in the rate of protein synthesis measured as 3H-leucine incorporation into acid precipitable material, and by increase in lactate dehydrogenase release into the medium. Hepatocytes from old rats were more susceptible to suppression of protein synthesis by GalN than cells of young ones. Preincubation of cells for 15 min with 9MC (41-560 nM) or PGE1 (10-100 nM), but not with TRK-100, before adding 10 mM GalN, led to a partial recovery of protein synthesis in both age groups. GalN increased LDH release and decreased ATP/ADP ratio to a similar extent in hepatocytes of young and old rats; both parameters were not altered by preincubation of cells with PGs. PGE1 and 9MC, but not TRK-100, elevated cyclic AMP content in hepatocytes of young but not old rats. Glucagon and forskolin similarly increased cyclic AMP content in cells of both young and old animals. These in vitro results suggest that PGE1 and some prostacyclin analogues might protect hepatocytes of both young and old rats from chemical damage, and stress the necessity for further research on cyto- and hepato-protection in the elderly.
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PMID:Prostaglandin cytoprotection of galactosamine-incubated hepatocytes isolated from young and old rats. 803 Aug 38

Hepatocytes isolated from rats by the collagenase perfusion method were cultured as monolayers at concentrations of 0.4-1.1 x 10(6) attached cells/dish (9 cm2) for 1-3 days and the effect of prostaglandins on their glycogenolysis was studied. By use of [14C]glycogen-labeled cells, prostaglandin E2 (PGE2) was found to have a stimulatory effect on glycogen degradation at high cell density (more than 0.8 x 10(6) cells/dish) in 1-day cultures. PGE2 was maximally effective at 10(-7) M, increasing [14C]release from cellular [14C]glycogen to 2-3 times the basal level after 1 h incubation, and to plateau level within 2 h. PGE1, 16,16-dimethyl PGE2 and PGF2 alpha had similar effects, but PGD2 and dinor-PGE1 (a metabolite of PGE1 and PGE2 in hepatocytes) had no effect. This prostaglandin-induced glycogen degradation was observed in 1-day cultures, with a maximum between 20-30 h, but not in 2-day and later cultures. Treatment of hepatocytes with pertussis toxin potentiated PGE2-stimulated glycogen degradation, indicating that the effect involves a different pathway from that for inhibition of glucagon- and epinephrine-stimulated glycogenolysis by E series prostaglandins reported previously.
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PMID:Stimulation of glycogen degradation by prostaglandin E2 in primary cultured rat hepatocytes. 832 15

Synovial fluid basic calcium phosphate (BCP) crystals are associated with severe destructive arthropathy. BCP crystals induce the secretion of matrix-degrading enzymes such as collagenase. No prophylactic or therapeutic agents are recognized to ameliorate the cartilage damage associated with BCP deposits in joints. As a chondroprotective effect of prostaglandins (PG) has been suggested, we studied the effect of misoprostol, a PGE1 analogue, on BCP crystal-induced mitogenesis and collagenase messenger RNA (mRNA) accumulation in human fibroblasts (HF). Mitogenesis was determined by 3H-thymidine incorporation assays and collagenase mRNA accumulation by Northern blot analysis, in HF stimulated with BCP crystals in the presence or absence of misoprostol. Misoprostol caused concentration-dependent inhibition of BCP crystal-induced mitogenesis. The inhibition of BCP-stimulated mitogenesis was not specific as misoprostol also inhibited the mitogenic response to 10% serum. There was only 50 (+/-5)% inhibition of serum-induced mitogenesis by misoprostol at 500 ng/ml, the concentration that completely inhibited BCP crystal-induced mitogenesis. Misoprostol also inhibited the accumulation of collagenase mRNA in BCP-stimulated HF by 63%. These data suggest that misoprostol may inhibit the synovial proliferation and cartilage degradation that accompany BCP crystal deposition.
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PMID:Misoprostol, a prostaglandin E1 analogue, inhibits basic calcium phosphate crystal-induced mitogenesis and collagenase accumulation in human fibroblasts. 836 90

1. Prostaglandin E2 (PGE2) is an autacoid that decreases proteoglycan synthesis, increases metalloprotease production by cultured chondrocytes, and can modulate some of the actions of interleukin-1 on cartilage. The objective of the present study was to characterize the subtype of prostaglandin E2 receptor present in bovine chondrocytes in culture. 2. Primary cultures of articular chondrocytes were prepared from slices of bovine carpal cartilage by sequential digestion with type III hyaluronidase, trypsin, type II collagenase, followed by overnight incubation in Dulbecco's Modified Eagle's Medium (DMEM) with type II collagenase, washing, and seeding at a density of 2 x 10(5) cells cm-2 in DMEM with 10% foetal bovine serum. 3. PGE2 and carbaprostacyclin induced dose-dependent increases in intracellular cyclic AMP in bovine chondrocytes in culture. The potencies of these compounds were different, and maximal doses of PGE2 and carbaprostacyclin had an additive effect. PGD2 induced a small increase in intracellular cyclic AMP only at a high concentration (10(-5) M). 4. PGE2 was more potent that the EP2 agonist 11-deoxy-PGE1 at inducing increases in intracellular cyclic AMP. The EP2 agonist butaprost, however, induced only a small increase at a concentration of 10(-5)M. 17-Phenyl-PGE2 (EP1 agonist), sulprostone and MB 28767 (15S-hydroxy-9-oxo-16-phenoxy-omega-tetranorprost-13E-enoic acid) (EP3 agonists) did not induce an increase in intracellular cyclic AMP at concentrations up to 10(-5)M. 5. The EP4 antagonist AH 23848B ([1 alpha(Z),2 beta, 5 alpha]-(+/-) -7-[5-[[(1,1'-biphenyl)-4-yl]methoxyl-2-(4-morpholinyl) -3-oxocyclopentyl]-5-heptenoic acid) antagonized PGE2 but not carbaprostacyclin effects on intracellular cyclic AMP. The Schild plot slope was different from 1 but this could be due to an interaction of PGE2 with IP receptors in high doses. The exact nature of the antagonism by compound AH 23848B could not be definitely established in these experimental conditions. 6. Neither PGE2 nor any of its analogues inhibited the increase in intracellular cyclic AMP induced by forskolin, and pertussis toxin did not alter the response to PGE2, suggesting that no Gi-coupled PGE2 receptors are present in these cells. Stimulation with PGE2 did not induce significant increases in intracellular inositol-trisphosphate levels nor increases in intracellular free calcium as determined by confocal microscopy, suggesting the absence of phospholipase-C-coupled or of calcium channel-coupled PGE2 receptors in bovine chondrocytes in these experimental conditions. 7. These results show for the first time that bovine chondrocytes in culture present a functional PGE2 receptor that has some pharmacological characteristics of an EP4 subtype, as well as an IP receptor.
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PMID:Characterization of the PGE2 receptor subtype in bovine chondrocytes in culture. 884 20

Gene expression of the matrix-degrading enzyme collagenase-1 in rabbit synoviocytes and human fibroblasts is down-regulated by prostaglandin E1 (PGE1) through a cyclic adenosine monophosphate (cAMP)-dependent pathway. In the current study, we examined the role of protein kinase A (PKA) in the PGE1-mediated effect on collagenase-1 gene expression. Collagenase-1 gene expression was rapidly induced several-fold above control both by a phorbol ester, 12-o-tetradecanoyl phorbol 13 acetate, and interleukin-1 beta (IL-1 beta) in HIG-82 synoviocytes. Treatment with PGE1 and forskolin increased PKA activity in the HIG-82 cells within 15 minutes of adding the stimulating agents. Two inhibitors of PKA, the isoquinoline-sulfonamide derivative, H-89 and a cAMP analog, RpcAMP, blocked the ability of PGE1 to down-regulate collagenase-1 gene expression. However, if PGE1 was added from 6 h to 30 minutes before the PKA inhibitor H-89, collagenase-1 gene expression was inhibited. Constitutive PKA activity was increased in HIG-82 synoviocytes stably transfected with an expression vector pCMV.C alpha that caused the HIG-82 cells to overexpress an active catalytic subunit of PKA. Cells stably transfected with an inactive, mutated C-alpha-variant showed no change in PKA activity. Collagenase-1 mRNA levels in TPA-stimulated cells were reduced to baseline levels in the pCMV.C alpha but not in the mutated C-alpha-transfected cells. These data show the importance of PKA in regulating collagenase-1 gene expression in a synoviocyte cell line.
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PMID:Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82. 910 67

The effects of prostaglandin (PG) I1 analog, SM-10906 (SM-6) and PGE1 on extracellular matrix formation and the release of cytokines by cultured normal human dermal fibroblasts (NDF) and hypertrophic scar fibroblasts (HSF) were compared in order to evaluate the clinical efficacy of PGs in preventing scar formation. In the present study, we measured type I collagen synthesis, collagenase activity, production of interleukin (IL)-6, IL-8, and transforming growth factor (TGF)-beta 1 and levels of adenosine 3,5-cyclic monophosphate (cAMP) in NDF and HSF cultured with or without PGs. The results demonstrated that HSF culture supernatants has a significantly higher level of type I collagen and TGF-beta 1 than those of NDF. However, the levels of collagenase activity and IL-8 in HSF were significantly lower in comparison to that of NDF. There was no substantial difference in IL-6 production between two types of culture cells. On the other hand, PGE1 and SM-6 significantly enhanced collagenase activity and raised the collagenase/type I collagen ratio in the HSF supernatants. In addition, both PGE1 and SM-6 increased production of TGF-beta 1, IL-8 and IL-6 and levels of cAMP in both cell types. However, they had no effect on the type I collagen synthesis of either types. These results suggest that, the stable PGI1 analog, SM-6, similarly acts as PGE1 in HSF by increasing the activity of collagenase.
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PMID:The mode of action of prostaglandin (PG) I1 analog, SM-10906, on fibroblasts of hypertrophic scars is similar to PGE1 in its potential role of preventing scar formation. 941 20

The search for a noncalcifying tissue material to be used for valve replacement application continues to be a field of extensive investigation. A series of porcine pericardial membranes was prepared by modifying the glutaraldehyde--treated tissues with albumin and subsequently immobilizing bioactive molecules like PGE1, PGI2 or heparin via the carbodiimide functionalities. The in vitro calcification and collagenase degradation of these modified tissues were studied as a function of exposure time. Furthermore, the biocompatibility aspects of such novel interfaces were established by platelet adhesion and fibrinogen adsorption. The results reported in this article propose that the treatment with antiplatelet agents such as albumin, heparin and prostaglandins (PGE1 or PGI2) change the surface conditioning of pericardial tissues, suggesting a possible role of deposited serum components in affecting mineralization process on bioprosthesis. Therefore, it is worthy to hypothesize that besides inhibiting the accumulation of calcium in the devitalized cells, the early formation of a conditioning layer on the bioprosthesis surface may affect salt precipitations, determining the propensity of the implant to calcify. More detailed studies are needed to understand the involvement of plasma proteins and cellular components of the recipient blood in tissue-associated calcification.
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PMID:Surface-immobilized biomolecules on albumin modified porcine pericardium for preventing thrombosis and calcification. 1053 11

Novel galactosylated neutral liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing" device were developed for hepatocyte-selective drug targeting. Distearoylphosphatidylcholine (DSPC)/cholesterol (Chol) (60:40) and DSPC/Chol/Gal-C4-Chol (60:35:5) liposomes were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [3H]Prostaglandin E1 (PGE1) and [14C]probucol were incorporated in liposomes as model lipophilic drugs. After intravenous injection of the liposomes, mice were sacrificed at suitable time periods, and the lung, liver, kidney, spleen, and heart were excised. DSPC/Chol/Gal-C4-Chol liposomes rapidly disappeared from the blood, and 85% of the dose had accumulated in the liver within 10 min compared with hepatic accumulation of DSPC/Chol liposomes of 12%. The liver was perfused with collagenase, and liver parenchymal cells (PC) and liver nonparenchymal cells (NPC) were separated by centrifugal differentiation to determine the cellular distribution. The PC/NPC ratios for DSPC/Chol/Gal-C4-Chol and DSPC/Chol liposomes were 15.1 and 1.1, respectively. The hepatic uptake of DSPC/Chol/Gal-C4-Chol liposomes, but not that of DSPC/Chol liposomes, was significantly inhibited by the predosing of galactosylated bovine serum albumin. [14C]Probucol and [3H]PGE1 incorporated in DSPC/Chol/Gal-C4-Chol liposomes was also efficiently delivered to the liver. In conclusion, newly developed galactosylated liposomes have been proven to be a useful carrier for hepatocyte-selective targeting that will have many practical applications.
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PMID:Novel galactosylated liposomes for hepatocyte-selective targeting of lipophilic drugs. 1116 27


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