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)

Degradation of interstitial collagens probably takes place through different enzymatic mechanisms than degradation of basement membrane and pericellular collagens. Interstitial collagens are resorbed under pathological and physiological conditions by collagenases which function extracellularly and cleave polypeptide chains in the collagen triple helix at specific loci resulting in solubilization from the fibril. Production of collagenase in humans is ascribable to fibroblast-like cells which can be stimulated to synthesize new enzyme for release outside of the cell. In several inflammatory conditions, such as rheumatoid synovitis, modulation of collagenase production is mediated by interactions with surrounding inflammatory cells. Monocyte-macrophages produce a stimulatory factor, which has homologies with interleukin 1, which not only increases collagenase synthesis but also PGE2 synthesis. The PGE2 in turn has profound effects on cellular function. Production of the mononuclear cell factor is modulated by several interactions including T lymphocytes and T lymphocyte products, collagen of the extracellular matrix and the Fc portion of immunoglobulins. It is probable, from analogies with other stimulants such as phorbol myristate acetate, that the increase in collagen synthesis is controlled at the level of transcription. Further regulation of collagenase action outside of the cell is probably accomplished by proteolytic activation of a latent collagenase zymogen and interactions with inhibitory proteins also produced by cells in the local environment of the resorptive process.
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PMID:Collagenases and collagen degradation. 628 82

The responses of cultured rabbit synovial fibroblasts to amorphous and microcrystalline calcium oxalate were compared with responses to MSUM. Like urate crystals, crystalline calcium oxalate (but not amorphous oxalate) caused marked stimulation of secretion of latent collagenase and PGE2 after 3 days of culture without significant change in cell protein or gross cellular morphology. Collagenase rose from undetectable levels in control cultures to 32.4 +/- 6.0 and 27.4 +/- 7.9 U/mg of cell protein for crystalline calcium oxalate and MSUM, respectively. PGE2 rose from a control level of 0.24 +/- 0.14 to 19.47 +/- 5.15 and 23 +/- 4.84 micrograms/mg of cell protein for crystalline calcium oxalate and sodium urate compared to 1.22 +/- 0.48 microgram for amorphous calcium oxalate. Although the crystalline species studied caused LDH in the media to increase threefold, this was minimal. Cell stimulation by amorphous oxalate and the crystals did not correlate with membranolytic potential as measured with an erythrocyte lysis assay. Stimulation of resident synovial cells by crystalline calcium oxalate and sodium urate may contribute to the chronic inflammation and destruction of joint tissues that occurs in oxalosis and gout.
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PMID:Stimulation of synovial fibroblasts by calcium oxalate and monosodium urate monohydrate. A mechanism of connective tissue degradation in oxalosis and gout. 629 14

Connective tissue destruction is a major characteristic of chronic rheumatoid arthritis (RA). Attempts at repair and fibrosis are also seen. This process is accompanied by local cellular and humoral inflammatory reactions. Production of large amount of collagenase and prostaglandin (PGE2) are demonstrated in vivo and can account for the pathogenesis. Long term cultures of adherent synovial cells from patient with RA produce also large amounts of collagenase and PGE2. Collagenase and PGE2 levels can be stimulated with a soluble factor (MCF), a monokine produced by monocyte-macrophages in culture. MCF production is modulated by cellular elements (T lymphocytes), by humoral elements (Fc fragments of immunoglobulin, immune complexes, antigens, lectins), by elements of the matrix (collagen). MCF appears to belong to the category of the interleukin 1. This factor also affects cell replication, collagen synthesis, hormonal response (to PGE2 and PTH). The monocyte-macrophages in this system appear to be the key between the immune and non-immune systems. Studies of MCF (one of the monocyte-macrophage products) will help the understanding of the pathogenesis of chronic inflammation such as RA and the designing and screening of new drugs potentially useful in destructive diseases.
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PMID:Aspects of resorption and formation of connective tissue during chronic inflammation in rheumatoid arthritis. 629 70

Blood mononuclear cells from patients with rheumatoid arthritis produce the lymphokine, leukocyte inhibitory factor (LIF) in response to collagens in vitro, and blood monocytes release prostaglandins (PGE2) and a factor, mononuclear cell factor (MCF) which stimulates collagenase and PGE2 production by cultured synovial cells. We therefore examined the effect of collagens on the production of PGE2 and MCF. Blood mononuclear cells from 6 patients with rheumatoid arthritis and 6 normal subjects were cultured in native human types I, II, or III collagen-coated tubes, or with streptokinase-streptodornase (SK-SD), and the supernatant media derived from these cultures analyzed for the presence of MCF, PGE2, and LIF. Types II and III collagens, as well as SK-SD, markedly stimulated MCF production by the cells from all 12 subjects (MCF activity, expressed as a mean stimulation index (SI) +/- SEM, was 43 +/- 12 for type II, 33 +/- 7 for type III, and 37 +/- 23 for SK-SD). Type I collagen was less stimulatory (mean SI 10 +/- 7). Cells from the patients with rheumatoid arthritis, but not the normal subjects, produced LIF in response to types II or III collagens but not to type I collagen. PGE2 production by blood mononuclear cells paralleled that of MCF, although abrogation of PGE2 release with indomethacin did not reduce MCF production. alpha chains purified from denatured collagens also stimulated MCF production. Using cells from patients with rheumatoid arthritis, type II collagen stimulated production of all three factors in the presence of polymyxin B or fibronectin-depleted serum, suggesting, respectively, that neither endotoxin nor fibronectin were responsible for their generation. Monocytes, purified from normal blood by an adherence technique, but not lymphocytes depleted of monocytes, released MCF and PGE2 when cultured with type II collagen. These results demonstrate that collagens can act as ligands to stimulate monocytes, as well as antigens to stimulate sensitized lymphocytes, to produce soluble factors that may contribute to the destruction of connective tissue.
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PMID:Collagens act as ligands to stimulate human monocytes to produce mononuclear cell factor (MCF) and prostaglandins (PGE2). 630 48

Supernatants harvested from peripheral blood mononuclear cells (PBMC) incubated either with the non-specific mitogen phytohaemagglutinin-P (PHA) or with the specific antigen tuberculin purified protein derivative for 72 h decreased collagen synthesis by dermal fibroblasts. PHA-induced mononuclear cell factors (PHA-MCF) responsible for decreases in collagen synthesis by dermal fibroblasts were localized by column chromatography on Sephacryl S-200 to fractions of 30,000-60,000 daltons. Proteolytic enzymes destroyed the activity of PHA-MCF, but after incubation with neuraminidase some activity of these factors remained. The activity of PHA-MCF was not inhibited by incubation with the monosaccharides L-fucose, L-rhamnose, N-acetylglucosamine, and alpha-methyl-D-mannoside but was partially destroyed by heating at 80 degrees C for 10 min. The factors were not mitogenic to PBMC. These factors did not appear to resemble any previously characterized factors produced by non-adherent mononuclear cells. The mechanism by which these factors decreased fibroblast collagen synthesis appeared complex. There was no detectable increase in the release of collagenase by fibroblasts, nor was a cytotoxic effect apparent. Increased PGE2 production by fibroblasts could not be related to the factor-induced decrease in fibroblast collagen synthesis.
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PMID:Mononuclear cell factors that inhibit fibroblast collagen synthesis. II. Properties of the factors. 630 50

In the present study, interleukin 1 (IL 1)-containing media from different sources, namely a murine macrophage cell line (P388D1), rabbit peritoneal macrophages, and human peripheral blood mononuclear cells, were compared for their effect on thymocyte proliferation and on collagenase and PGE2 secretion by chondrocytes. A high correlation was found between the enhancement of thymocyte proliferation and the induction of collagenase and PGE2 secretion by chondrocytes. Furthermore, a highly purified IL 1-like factor, namely mononuclear cell factor (MCF) was also active on chondrocytes. The addition of highly purified IL 2 to rabbit chondrocytes had no effect on collagenase and PGE2 secretion induced by IL 1-containing media. Our findings suggest that the factor which induced collagenase and PGE2 secretion by rabbit chondrocytes was an IL 1-like factor. Thus, collagenase secretion by chondrocytes may be used as an IL 2-insensitive assay for the detection of IL 1-like factors.
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PMID:Interleukin 2-independent stimulation of rabbit chondrocyte collagenase and prostaglandin E2 production by an interleukin 1-like factor. 632 70

Piroxicam and other antiarthritic drugs were compared with respect to their effects on T-lymphocyte/monocyte/rheumatoid synovial cell interactions leading to inflammatory mediator production. Piroxicam inhibited PGE2 formation by blood mononuclear cells, but was less potent than indomethacin. Both drugs enhanced suboptimal phytohemagglutinin (PHA)-stimulated tritiated thymidine (3H-TdR) incorporation by mononuclear cells, although optimal responses were less affected. Exogenous interleukin-2 (IL-2) enhanced suboptimal but not optimal PHA responses, and the effects of the cyclo-oxygenase inhibitors were overcome by exogenous PGE2. Thus piroxicam and indomethacin prevented the inhibition by endogenous monocyte-derived PGE2 of IL-2 secretion and activity. Other antiarthritic drugs, including antimalarials, immunosuppressive agents and gold salts, inhibited PHA-induced lymphocyte proliferation regardless of the level of stimulation. Mepacrine and chloroquine were more effective in inhibiting the release of mononuclear cell factor (MCF) that stimulated PGE2 synthesis by synovial cells. Cyclosporin-A, azathioprine and 6-mercaptopurine were more potent as antiproliferative agents than as inhibitors of mediator release. Sodium aurothiomalate and aurothioglucose selectively interfered with lymphocyte-mediated amplification of MCF release, whereas auranofin inhibited spontaneous production of monocytes and the action of MCF on synovial cells. In rheumatoid synovial cells, piroxicam and indomethacin inhibited PGE2 production but not collagenase release. Suppression of MCF release could lead indirectly to reduction of IL-2 and collagenase as well as PGE2 production and consequently to more profound inhibition of immunologically-mediated inflammation.
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PMID:Effects of piroxicam on mononuclear cells. Comparison with other antiarthritic drugs. 633 79

Rheumatoid Arthritis is a chronic, usually progressive inflammatory disorder of joints in which the immune system plays a central role in the pathogenesis. In its classic form, the synovial tissues from severely affected joints are densely infiltrated with HLA-DR bearing T-lymphocytes (primarily OKT4+/Leu3+ subset) and macrophage-like cells. Moreover, these tissues, as demonstrated by ex vivo culture, spontaneously produce high levels of a multitude of inflammatory mediators, such as collagenase, PGE2, interleukin 1 and fibroblast activating factors, indicating that the cells infiltrating the synovium are "activated". The action of these various inflammatory mediators on different target substances or cells (collagen, fibroblasts, chondrocytes, osteoclasts, etc.) most likely produce the characteristic pattern of joint pathology. Recent data indicate that this classic form of synovitis tends to be associated with peripheral anergy and other qualitative and quantitative abnormalities in the peripheral blood mononuclear cells. Repeated leukapheresis can induce substantial, although transient, clinical improvement in patients with these classic features, probably as a consequence of disrupting T-lymphocyte traffic. Rheumatoid synovitis, however, is highly heterogeneous, but can be categorized into subsets. For example, a subset of patients with highly active clinical rheumatoid arthritis exists which do not exhibit the classic features of disease. Synovial tissues from this patient subset are sparsely infiltrated by T-lymphocytes but contain mainly macrophages and fibroblasts, as well as prominent lining layer fibrin deposition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukapheresis and pathogenetic mechanisms in rheumatoid arthritis. 633 86

Prostaglandin E2 (PGE2) over the concentration range 10(-5)-10(-7) M stimulated calcium uptake in osteoclastic-enriched populations isolated by sequential collagenase digestions of newborn rat calvaria. This effect was on initial calcium uptake occurring at 5 min at 37 degrees C but was not present when isotopic equilibrium was approached (60 min). Prostacyclin (PGI2, PGE1 and PGF2 alpha) stimulated osteoclastic calcium uptake in a similar manner, but with slightly smaller effects than PGE2. Under identical conditions, significant effects of PG were not observed in osteoblastic cells isolated from the same bones by extended collagenase digestions. Combined treatment with PGE2 and parathyroid hormone (PTH) at concentrations which produced no individual effects resulted in a significant increase in calcium uptake in osteoclastic cells. During a 48-h culture period, osteoblastic populations released significantly greater amounts of PGE2 than osteoclastic populations. Pre-incubation for 1 h at 37 degrees C with the prostaglandin cyclo-oxygenase antagonists, indomethacin and flufenamic acid, had no effect on calcium uptake in osteoclastic cells, but resulted in significant decreases in osteoblastic cells. The PGE2-induced increase in calcium uptake on osteoclastic cells was not altered by indomethacin or flufenamic-acid pretreatment. However, after treatment with these inhibitors, a significant response to PGE2 was observed in osteoblastic cells.
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PMID:Effects of prostaglandins on rat calvarial bone-cell calcium. 639 25

The biosynthesis of prostaglandins by isolated epithelial glandular and stromal cells was studied after collagenase digestion of endometrium collected from women at various stages of the menstrual cycle. Homogenates of the separate cell types were incubated for 60 minutes with 2.08 micrograms 1(14)C arachidonic acid and the products separated by thin layer chromatography. Both glandular and stromal homogenates synthesised PGF2 alpha. More PGF2 alpha was synthesised by glandular epithelium separated from both proliferative and secretory endometrium than by stroma. The ratio of PGF2 alpha/PGE2 was greater in glands and stroma isolated from secretory than proliferative endometrium. Small but significant amounts of 6-keto-PGF1 alpha were produced by all cell types. These results suggest that the increased synthesis of PGF2 alpha from secretory endometrium is due, at least in part, to increased activity of cyclo-oxygenase enzyme in the glandular epithelium.
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PMID:Prostaglandin production from homogenates of separated glandular epithelium and stroma from human endometrium. 644 Nov 84


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