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 matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro 31-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro 31-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on interleukin-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro 31-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro 31-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.
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PMID:Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro. 166 94

Cystic fibrosis is associated with an cAMP-regulated channel defect, which has been evidenced in many cell types including B lymphocytes. To document a B-cell dysfunction potentially related to this defect, we studied the in vitro IgG production by lymphocytes from 11 cystic fibrosis patients. B lymphocytes were co-cultured with autologous monocytes and stimulated with Staphylococcus aureus Cowan or with Nocardia-delipidated cell mitogen in the presence of low concentrations of IL2. Cystic fibrosis patients' cells produced amounts of IgG comparable with that of normal and control patients' cells. However, dexamethasone (10(-7) mol l-1) had no effect on the response of cystic fibrosis patients' cells, whereas it enhanced that of the latter two groups. This resistance of cystic fibrosis cells was true with concentrations of dexamethasone up to 10(-6) mol l-1, whereas this agent induced a dose-related enhancement from 10(-8) to 10(-6) mol l-1 in cultures of normal cells. Co-culture experiments showed that cystic fibrosis B lymphocytes themselves are resistant to the effect of dexamethasone. In contrast dexamethasone normally suppressed the anti-CD3 antibody-induced response of cystic fibrosis T cells in the presence of IL2 and the IL1 alpha- or beta-induced collagenase production of cystic fibrosis fibroblast cell lines. Thus cystic fibrosis B lymphocytes exhibit a selective defect which may interfere with the normal interactions between the hormonal and immune systems and may participate in the sensitivity of cystic fibrosis patients to bacterial bronchopulmonary infections.
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PMID:Cystic fibrosis patients' B-lymphocyte response is resistant to the in vitro enhancing effect of corticosteroids. 196 24

The processing of precursor interleukin 1 beta (IL1 beta) by elastase, cathepsin G, and collagenase, the major proteases released at sites of inflammation, was investigated using recombinant pro-IL1 beta. Each of these proteases cleaved the 31-kDa inactive precursor to a form similar in size and specific activity (greater than 10(8) units/mg) to the 17-kDa mature protein isolated from activated monocytes. Elastase, collagenase, and cathepsin G cleaved the IL1 beta precursor at distinct sites which are amino-terminal to the monocyte-processing site, Ala-117 (Cameron, P., Lumjuco, G., Rodkey, J., Bennett, C., and Schmidt, J. A. (1985) J. Exp. Med. 162, 790-801). Amino-terminal sequencing of the products of digestion by elastase and cathepsin G determined that resultant active IL1 beta proteins contained an additional 13 or 3 amino acids relative to mature IL1 beta. Synovial fluid collected from patients with inflammatory polyarthritis and bronchoalveolar lavage fluid from patients with sarcoidosis supplied similar processing activity(s). Control fluids from patients who had no symptoms of inflammatory disease did not exhibit processing activity. Lavage fluids that processed precursor IL1 beta were demonstrated to contain cathepsin G and/or elastase activity, whereas controls were negative. Because a significant fraction of IL1 beta may be secreted from monocytes as the inactive 31-kDa precursor (Hazuda, D. J., Lee, J. C., and Young, P. R. (1988) J. Biol. Chem. 263, 8473-8479, Bomford, R., Absull, E., Hughes-Jenkins, C., Simpkin, D., and Schmidt, J. (1987) Immunology 62, 543-549, and Mizel, S. B. (1988) in Cellular and Molecular Aspects of Inflammation Poste, G., and Crooke, S., eds) pp. 75-93, Plenum Publishing Corp., New York), these results suggest that in vivo the IL1 beta precursor can be processed after secretion by any of several proteases released at inflammatory sites.
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PMID:Processing of precursor interleukin 1 beta and inflammatory disease. 215 47

Fibroblasts from normal human adult skin were cultured in vitro in the presence and absence of different concentrations of pentoxifylline or a pentoxifylline analog, A81-3138 (10(-1)-10(3) micrograms/ml). Similar concentration dependent reductions in normal proliferation of fibroblasts in fetal calf serum-driven subconfluent cultures were detected following treatment with pentoxifylline or A81-3138. Fibroblasts assayed as confluent cultures produced sub-normal amounts of collagen, glycosaminoglycans (GAGs), and fibronectin in a fashion dependent upon the concentration of pentoxifylline. In contrast, fibroblasts exposed to pentoxifylline elaborated double the collagenase activity produced by normal, untreated fibroblasts. The reduced proliferation and reduced synthetic activities were not due to a lethal toxic effect on fibroblasts by pentoxifylline and A81-3138, nor was the reduction in collagen synthesis simply due to an inability to secrete newly synthesized intracellular collagen. Unlike pentoxifylline-induced inhibition of collagen and fibronectin production, which was detected only in cultures supplemented with serum, pentoxifylline inhibits, to a similar degree, both constitutive and serum-driven production of GAGs. The addition of IL1 beta (2.5 and 10.0 U/ml) to serum-driven fibroblast cultures resulted in greater proliferation, which was inhibitable by the presence of pentoxifylline and A81-3138 as anti-fibrotic agents in certain disorders of fibrosis.
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PMID:Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity. 253 14

The action of purified rheumatoid synovial collagenase and human neutrophil elastase on the cartilage collagen types II, IX, X and XI was examined. At 25 degrees C, collagenase attacked type II and type X (45-kDa pepsin-solubilized) collagens to produce specific products reflecting one and at least two cleavages respectively. At 35 degrees C, collagenase completely degraded the type II collagen molecule to small peptides whereas a large fragment of the type X molecule was resistant to further degradation. In contrast, collagen type IX (native, intact and pepsin-solubilized type M) and collagen type XI were resistant to collagenase attack at both 25 degrees C and 35 degrees C even in the presence of excess enzyme. Mixtures of type II collagen with equimolar amounts of either type IX or XI did not affect the rate at which the former was degraded by collagenase at 25 degrees C. Purified neutrophil elastase, shown to be functionally active against soluble type III collagen, had no effect on collagen type II at 25 degrees C or 35 degrees C. At 25 degrees C collagen types IX (pepsin-solubilized type M) and XI were also resistant to elastase, but at 35 degrees C both were susceptible to degradation with type IX being reduced to very small peptides. Collagen type X (45-kDa pepsin-solubilized) was susceptible to elastase attack at 25 degrees C and 35 degrees C as judged by the production of specific products that corresponded closely with those produced by collagenase. Although synovial collagenase failed to degrade collagen types IX and XI, all the cartilage collagen species examined were degraded at 35 degrees C by conditioned culture medium from IL1-activated human articular chondrocytes. Thus chondrocytes have the potential to catabolise each cartilage collagen species, but the specificity and number of the chondrocyte-derived collagenase(s) has yet to be resolved.
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PMID:Susceptibility of cartilage collagens type II, IX, X, and XI to human synovial collagenase and neutrophil elastase. 284 Nov 21

Interleukin 1 (IL 1), a cytokine expressed from a number of cell types, plays a vital part in immune and inflammatory processes. Epidermal IL1-like activity, also known as epidermal cell thymocyte-activating factor (ETAF), is associated with whole skin, epidermis, Langerhans cells and cultured keratinocytes and keratinocyte cell lines. We show that preparations of heat-separated epidermis possess abundant IL1/ETAF activity as indicated by PGE/collagenase induction in cultured synovial cells and proliferation of mouse thymocytes. However, using cDNA probes to interleukin-1 alpha and beta we show that freshly isolated heat-separated epidermis from healthy adult donors contains only a slight detectable level of IL1 alpha mRNA by dot blot analysis and no IL1 beta and IL1 alpha mRNA by Northern blot analysis. The implications of these observations will be discussed.
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PMID:IL1/ETAF activity and undetectable IL1 beta mRNA and minimal IL1 alpha mRNA levels in normal adult heat-separated epidermis. 326 28

Recently, we demonstrated that normal human epidermis contains IL1. The present work analyses further the significance of this observation by comparing the quantities of epidermal IL1 to those of 7 internal organs in normal rat. Epidermal PGE2 stimulating activity was 200 to 900 fold higher than in the internal organs. Similar results were obtained for the collagenase stimulatory activity and the comitogenic effect on thymocytes. Epidermal IL1 activity in membrane preparations was more than 100 times lower than the activity of the cytosol containing supernatant from the epidermal homogenate. Biochemical analysis by HPLC identified a MW approximately 17 Kd form with a pI 5.7 and a MW approximately 30 Kd form. These results 1) confirm the presence of high amounts of preformed IL1 in normal unstimulated epidermis, 2) show that, compared to 7 internal organs, the epidermis contains the highest activity, 3) suggest that epidermal IL1 is mainly situated in the cytosol, 4) identify a MW approximately 17 Kd form with a pI 5.7, as well as a MW approximately 30 Kd form which might represent an IL1 precursor, 5) demonstrate the copurification of PGE2 and collagenase stimulatory and thymocyte comitogenic activity and 6) give a starting reference for the in vivo study of IL1 activity in pathologic situations.
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PMID:Normal epidermis contains high amounts of natural tissue IL 1 biochemical analysis by HPLC identifies a MW approximately 17 Kd form with a P1 5.7 and a MW approximately 30 Kd form. 348 28

Leukotriene C4 (LTC4), a mediator generated by a variety of inflammatory cells, participates in several physiological and pathological processes. It has been shown that LTC4 stimulates collagen synthesis by fibroblasts, suggesting a role in collagen turnover. However, the possible effect of this mediator on collagen degradation has not been examined. In this study we explored the role of LTC4 in the modulation of fibroblast interstitial collagenase and TIMP-1. Confluent cultures of three human normal lung fibroblast cell lines, and one derived from idiopathic pulmonary fibrosis (IPF) were exposed to LTC4 0.1, 1 and 10 nM, and to IL-1 beta as positive control. Collagenase and TIMP mRNAs expression were analyzed by Northern blot followed by densitometric scanning. Immunoreactive procollagenase was detected by immunoblot, and collagenase activity was measured using [3H]collagen. Our results showed that LTC4 enhanced several-fold collagenase mRNA expression in collagenase-producing fibroblasts, and induced the expression of the enzyme mRNA in collagenase-nonproducing fibroblasts, both in normal and IPF derived cell lines. LTC4 1 nM induced the highest response. Collagenolytic activity and immunoreactive collagenase paralleled collagenase mRNA expression. Interestingly, simultaneous exposure of fibroblasts to LTC4 plus IL-1 failed to show additive effects. Moreover, in two cell lines the combination resulted in a decrease of collagenase mRNA expression compared with both mediators separately. TIMP mRNA levels were not significantly modified by LTC4, nor IL1 beta. Our findings suggest that LTC4 plays a role in the modulation of fibroblast collagenase, and it may participate in extracellular matrix remodeling during lung inflammation.
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PMID:Leukotriene C4 upregulates collagenase expression and synthesis in human lung fibroblasts. 798 Dec 29

Keratoconus, a bilateral corneal disease, is characterized by modifications in corneal shape and thinning of the stroma. It affects young people. From a biochemical point of view, a decrease in collagen content, probably due to the high collagenase activity, has been reported. In these experiments, we have studied the membrane receptors for interleukin 1 alpha, and the corresponding dissociation constant (KD). We also investigated synthesis of prostaglandin E2 (PGE2) and collagen, as well as kinetics of cyclooxygenase. Data from normal human corneas and from keratoconus were compared. Fibroblasts from keratoconus proved to bear four fold more IL1 binding sites than those from normal cornea, with similar KD. Both types of cells synthesize prostaglandin E2, even if IL1 is not added to the medium, but the keratoconus cells produce ten times more than the normal cornea cells. When the cells are stimulated with IL1, synthesis of PGE2 strongly increases and the amounts produced by keratoconus cells are always higher than those of the normal cornea cells. Kinetics of the cyclooxygenase show that Vmax. is 10 times higher in keratoconus than in normal cornea cells; Km's are the same. The amounts of collagen synthesized by keratoconus cells are slightly lower than those of normal cornea cells. Addition of IL1 to the cultures enhances synthesis of collagenase by the cells and decreases collagen found in the culture media. The drop of collagen is more important in keratoconus than in normal cornea cell cultures.
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PMID:Modification of prostaglandin E2 and collagen synthesis in keratoconus fibroblasts, associated with an increase of interleukin 1 alpha receptor number. 840 71

The potentialities of a new non-invasive optical scanning microscopy technique were evaluated through 3D analysis of chondrocyte-matrix interactions. Five different 2D or 3D culture systems were used: (1) MonoLayer (ML) of human chondrosarcoma cell line; (2) rat or human chondrocytes encapsulated in Alginate Bead (AB); (3) human chondrocytes encapsulated in Alginate Sponge (AS); (4) Rat Femoral Head Cap (RFHC); (5) slices of knee human Osteoarthritic Cartilage (HOAC). Chondrocytes ML, AB, RFHC were incubated for 24 h in vitro in the presence of recombinant human interleukin1-beta (rhIL1-beta) and the effects on cytoskeleton organisation (F-actin filament), Focal Adhesion Kinase (FAK) expression (tyrosine kinase), collagenase B expression (metalloprotease) were studied. Furthermore, the production of intracellular IL1-beta by LPS- or rhIL1-beta-stimulated chondrocytes was shown to be partly suppressed by rhein (active metabolite of diacerhein) in all culture systems. This high resolution light microscopy gave complementary information that could be important for a better understanding of the interaction of chondrocytes with the extracellular matrix in a variety of culture devices.
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PMID:The role of 3D-microscopy in the study of chondrocyte-matrix interaction (alginate bead or sponge, rat femoral head cap, human osteoarthritic cartilage) and pharmacological application. 1091 89


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