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)

In advanced osteoarthritis, all of the cartilaginous components are lost from the joint surface. Although mechanisms exist for proteoglycan degradation, there is not known to be any system for removal of the collagen. This study suggests that the loss of the collagen components may be a function of articular cartilage collagenase. The enzyme in normal human cartilage is bound to an inhibitor and appears to be present in very small amounts. Attempts to demonstrate collagenase activity in ground human articular cartilage or in its lysosomal fraction were unsuccessful. 7-Day cartilage tissue cultures also failed to demonstrate the presence of the enzyme; but the same culture fluid, incubated with trypsin, showed significant degradation of collagen, suggesting that trypsin destroyed the inhibitor. 7-Day culture fluids were then chromatographed on a heparin-charged Sepharose 4B affinity column that had been activated with cyanogen bromide. This removed the inhibitor, and the chromatographed fluid from osteoarthritic cartilage released 42% of the incorporated counts of the collagen substrate, whereas normal cartilage released 10.1% and a trypsin control, 6.4%. Electrophoresis of the degradation products of the enzyme-collagen complex incubated at 37 degrees C revealed breakdown was complete to small dialyzable fragments, while at 25 degrees C larger fragments were split off.
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PMID:Collagenase and collagenase inhibitors in osteoarthritic and normal cartilage. 18 66

The aim of this study was to describe the normal distribution of calcitonin gene-related peptide (CGRP) and substance P (SP) containing fibres in the knee joint of the mouse and to obtain insight into the changes in innervation associated with degenerative processes in the joint. Arthrosis was induced by a single subpatellar intra-articular injection of bacterial collagenase. After decalcification in EDTA solutions, the CGRP and SP fibres were visualized by peroxidase-antiperoxidase pre-embedding immunocytochemistry for light microscopy. Control experiments on the mouse brain as a reference for the effect of EDTA on the immunostaining showed that the decalcification procedure with EDTA had not impaired the immunostaining. A rich innervation of thin varicose CGRP and SP immunoreactive fibres was found in most peri- and intra-articular tissue components. The periosteum, synovial tissues, the joint capsule and the intra-articular fat tissues were richly innervated. Less intense innervations were also found in the subchondral bone plates of the tibio-femoral joint and of the patella. Fibres were also found in the soft tissues between the patellar tendon and the femoral groove. No differences could be found between the location of CGRP and SP fibres with respect to the localization in the joint, but generally more CGRP fibres were found. The collagenase-induced osteoarthrosis was characterized by sclerosis of the subchondral bone, patellar dislocation, osteophyte formation, synovial proliferation and by severe cartilage abrasion, particularly on the medial side of the femoro-tibial joint. The overall distribution of CGRP and SP fibres was the same as in the control joints. However, major differences were found in all studied joints at specific locations around the cruciate ligaments, in the synovium around the patella, in the soft tissues lateral of the patella and in plica tissue between the patella and femoral groove. The CGRP and SP innervation was no longer detectable by immunolabelling with the antibodies. With a polyclonal antibody to the growth associated protein GAP-43/B-50, signs of degenerated axonal profiles were observed in these locations. At other peripheral locations, such as the muscles, the GAP-43/B-50 distribution was normal. In conclusion, the present study provides detailed information on the localization of CGRP and SP fibres, which may be involved in pain perception. Knowledge of the changes that occur during arthrosis may give more insight into the clinical symptoms.
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PMID:Calcitonin gene-related peptide, substance P and GAP-43/B-50 immunoreactivity in the normal and arthrotic knee joint of the mouse. 128 63

To elucidate the mechanisms for the presence of immunoglobulins and human serum albumin (HSA) in articular cartilage from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), the recovery of these molecules was determined in several elution steps. These steps included serial elutions with a neutral buffer to extract entrapped molecules, elution with 6 M guanidine hydrochloride to extract molecules bound by noncovalent interactions, and digestion of cartilage with bacterial collagenase to release molecules covalently bound to cartilage matrix proteins. Significantly more IgG than HSA was recovered with 6 M guanidine after serial elutions with neutral buffer from the cartilages of patients with both RA and OA, consistent with the binding of IgG by antigen-antibody bonds. Degradation of cartilage with collagenase released additional IgG and HSA. Analysis of the IgG and HSA, recovered with guanidine or with collagenase, using SDS-PAGE and transfer blotting, indicated for the first time the presence of disulfide bonds between these molecules and cartilage matrix molecules.
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PMID:IgG is bound by antigen-antibody bonds and some IgG and albumin are bound by intermolecular disulfide bonds to cartilage in rheumatoid arthritis and osteoarthritis. 131 84

We investigated the in-vivo proteoglycan synthesis in specific areas of murine knee joint articular cartilage after the induction of degenerative joint disease by means of 35S-sulphate autoradiography. Degenerative joint disease was induced either by direct interference with cartilage metabolism (papain and iodoacetate), or by the induction of joint instability (collagenase). Injection of iodoacetate and papain led to inhibition of proteoglycan synthesis mainly in the central parts of the patellae, patellaris femoris and the central part of the medial tibial plateau. Articular cartilage adjacent to the strongly inhibited areas frequently showed a significantly enhanced synthesis of proteoglycans. A strong inhibition of proteoglycan synthesis was observed in the central part of the medial plateau after collagenase injection while other cartilage sites and joint structures such as the capsule and ligaments were stimulated in their proteoglycan synthesis. This study shows that the localization of changes in cartilage metabolism in degenerative joint disease of the knee might be related to differences in the pathogenetic mechanism in different variants of this common joint disorder.
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PMID:Proteoglycan synthesis and osteophyte formation in 'metabolically' and 'mechanically' induced murine degenerative joint disease: an in-vivo autoradiographic study. 132 Mar 94

Interleukin-1 (IL-1) has protean effects in the pathogenesis of rheumatoid arthritis (RA). These effects include production of prostaglandins and collagenase from rheumatoid fibroblasts as well as upregulation of adhesion molecule expression on these cells. IL-1 can activate monocytes and neutrophils, as well as promote the growth of fibroblasts and endothelial cells. Recently, a novel interleukin-1 receptor antagonist protein (IRAP) has been isolated, purified, cloned, and expressed, which may modulate the effects of IL-1. In this study, we present data demonstrating that macrophages isolated from human RA synovial tissues express both IL-1 and IRAP genes. In addition, RA synovial tissue macrophages and lining cells display IL-1 and IRAP antigenic expression by immunohistochemistry. In contrast, osteoarthritis synovial tissues, as compared to RA, have fewer IL-1 and IRAP-positive macrophages. Thus, the production of IL-1 balanced by IRAP may affect the joint destruction found in these diseases.
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PMID:Expression of interleukin-1 and interleukin-1 receptor antagonist by human rheumatoid synovial tissue macrophages. 139 21

The extracellular matrix (ECM) of articular cartilage is subject to a steady remodelling process. The collagenous components of the ECM are characterized by a very low rate of metabolism, whereas the proteoglycans exhibit an active turnover. The main proteolytic enzymes degrading the ECM components are collagenase, gelatinase and stromelysin. These enzymes undergo under pathological circumstances a remarkable enhancement of synthesis and activity. Although each of these enzymes appears to degrade one ECM component specifically, there is evidence for synergistic effects of most of them. Gelatinase acts synergistically with collagenase in degrading insoluble interstitial collagens and stromelysin activates collagenase. Thus a cascade mechanism may exist in which the cartilage-ECM is completely degraded. Yet, it is not crucial which part of the ECM (collagens or proteoglycans) is primarily degraded. The integrity of the ECM rather depends on the balance between anabolic and catabolic processes, the upset of which results in damage of the articular cartilage. Cartilage destruction in rheumatoid arthritis and osteoarthritis is considered to be a result of this imbalance in favour of the catabolic processes. This would lead to a decrease in proteoglycans which causes fibronectin deposition in the cartilage ECM. Due to chemotaxic effects of fibronectin on fibroblasts, the enrichment of this glycoprotein in the ECM gives rise to cartilage fibrosis and early degeneration.
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PMID:[Proteolytic enzymes and the destruction of articular cartilage in arthritis and chronic polyarthritis]. 164 88

Interleukin-1 (IL-1) plays an important role in cartilage destruction associated with inflammatory and degenerative arthritis because of its ability to induce matrix degrading enzymes. Previously, we have shown that the IL-1-induced chondrocyte protease activity was inhibited by transforming growth factor-beta (TGF-beta). In this paper, we show that TGF-beta inhibits the IL-1-induced synthesis of collagenase and stromelysin by reducing the steady-state mRNA levels in rabbit articular chondrocytes. We further demonstrate that TGF-beta-treated chondrocytes show reduced 125I-IL-1 binding that returns to a normal level when TGF-beta is removed from the culture medium. The inhibitory effect of TGF-beta is observed for both naturally occurring as well as fibroblast growth factor (FGF)-inducible binding sites (receptors). Scatchard analysis of receptor-ligand interactions demonstrate that the reduced binding is due to a reduction in the number of receptors for IL-1 and is not due to changes in affinity. Affinity cross-linking studies suggest that control chondrocytes contain two major cross-linked bands of Mr = 116 and 80 kDa and a minor band of Mr = 100 kDa. FGF-treated cells show enhanced levels of all the bands, plus an additional 200-kDa band. TGF-beta treatment of chondrocytes results in the reduction of all of these bands in both control as well as FGF-induced cells. These observations suggest that the ability of TGF-beta to down-regulate the IL-1 receptor may be a mechanism by which it exerts its effects in antagonizing the IL-1 activity on chondrocytes.
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PMID:Transforming growth factor-beta inhibition of interleukin-1 activity involves down-regulation of interleukin-1 receptors on chondrocytes. 164 57

Destructive joint changes in rheumatoid arthritis (RA) are thought to be mediated in part by the neutral proteinases collagenase and stromelysin. Collagenase messenger RNA (mRNA) has been previously localized to the synovial lining layer. In this study, synovial tissue from 8 patients with RA and 2 patients with osteoarthritis was examined for proteinase production by in situ hybridization. Stromelysin mRNA localized predominantly to the synovial lining layer cells. In serial sections, collagenase mRNA was shown to be localized to the same tissue areas as those producing stromelysin mRNA, and grain counts revealed a direct correlation between production of stromelysin mRNA and production of collagenase mRNA. All patients with RA were producing collagenase and stromelysin mRNA in detectable amounts. One of 2 osteoarthritis patients was producing these metalloproteinases, but in levels below those found in the RA patients. These data support the identity of the synovial lining cells as the major synovial cells producing collagenase and stromelysin in RA and provide new evidence for the coordinate production of collagenase and stromelysin in RA in vivo.
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PMID:In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. 165 7

The expression of messenger RNA encoding neutral metalloproteinases and the tissue inhibitor of metalloproteinases (TIMP) in human arthritic synovium was evaluated in situ, using RNA probes. Interstitial collagenase and stromelysin were expressed by synovial lining cells in patients with active rheumatoid arthritis (RA). Proteinase messenger RNA was found both in cells expressing mononuclear phagocyte antigens and in cells that were negative for the antigens. TIMP was also expressed predominantly along the synovial lining layer. In highly inflammatory RA, TIMP expression appeared less intense than that of the proteases. In osteoarthritic synovium, TIMP was expressed at easily detectable levels, whereas the expression of collagenase and stromelysin was less prominent. The balance between expression of the metalloproteinases and of the metalloproteinase inhibitor in synovium appears to be altered during inflammation. These results are consistent with the notion that synovium plays different roles in the cartilage damage of RA and of osteoarthritis.
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PMID:Expression of metalloproteinases and metalloproteinase inhibitor in human arthritic synovium. 165 8

In situ hybridization was used to localize and quantify gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Collagenase, tissue inhibitor of metalloproteinases (TIMP), HLA-DR, and complement (C2 and C3) gene expression was studied in synovial tissue from 23 patients with RA, OA, or other inflammatory arthropathies. Gene expression was highly compartmentalized: Collagenase, TIMP, and C2 messenger RNA (mRNA) were localized primarily to the synovial lining layer; HLA-DR mRNA was prominent in the lining and in some sublining lymphoid aggregates; the C3 probe hybridized only to sublining lymphoid aggregates. Relative mRNA levels were quantified using computer-assisted image analysis. There was significantly more collagenase, C2, C3, and HLA-DR mRNA in RA compared with OA patients. However, TIMP mRNA levels were similar in RA and OA. Expression of collagenase, TIMP, C2, C3, and HLA-DR genes correlated with the degree of synovial inflammation. The effect of intraarticular corticosteroid injection on synovial tissue gene expression was studied using serial percutaneous synovial biopsy samples from the knees of 3 RA patients. Joints were biopsied, injected with triamcinolone, and rebiopsied 1-2 weeks later. Histologic inflammation scores were lower in posttreatment synovia. Collagenase and TIMP mRNA, although abundant in presteroid samples, were nearly undetectable in post-steroid tissues. HLA-DR mRNA levels also were significantly decreased. C2 and C3 hybridization significantly decreased in 2 of 3 patients and 1 of 3 patients, respectively. Hence, clinical response to intraarticular steroid therapy was accompanied by histologic improvement and decreased expression of genes that play a role in articular destruction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids. 165 9


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