Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the nature of cytokines synthesized by human osteoarthritic (OA) synovium, particularly interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha). We examined the capacity of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) to block the synthesis of metalloproteases (collagenase and stromelysin), IL-1 beta, and IL-6 in osteoarthritis (OA) synovium. Human OA synovium were incubated in the presence or absence of lipopolysaccharide (LPS) or increasing concentrations of rhIL-1ra. The determinations of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-1ra in culture medium were carried out using specific ELISA. Although both IL-1 isoforms and TNF alpha could be produced by OA synovium, IL-1 beta was the predominant cytokine synthesized either in the presence or absence of LPS. Treatment of the OA synovium with an increasing concentration of rhIL-1ra (0-10 micrograms/ml) showed a dose dependent reduction of both metalloproteases and IL-6. Maximal inhibition was 70% for collagenase, 80% for stromelysin, and 76% for IL-6. LPS treated synovium also showed a consistent suppression of metalloproteases and IL-6, although a higher IL-1ra concentration was required. Conversely, IL-1 beta production was not inhibited by IL-1ra, irrespective of the concentration used and whether the membranes were LPS stimulated. These data showed that IL-1 appears to be the major autocrine cytokine involved in the stimulation of metalloproteases and IL-6 synthesis in OA synovium.
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PMID:Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. 775 12

Evidence indicates that breakdown of articular cartilage resulting in the loss of normal joint function is the distinctive feature of osteoarthritis. Degradation of cartilage extracellular matrix components involves the action of at least 2 classes of proteinases: serine proteinases and metalloproteinases. Receptors have been described on a wide range of cell lines for many such proteinases [urokinase-type plasminogen activator (u-PA), plasminogen/plasmin, collagenase], which subsequently activate each other on the solid phase of the cell surface, leading to cartilage destruction. We review the leading role of u-PA and its receptor (u-PAR) in cartilage degradation.
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PMID:Plasminogen activator and receptor in osteoarthritis. 775 14

Oral administration of doxycycline has been shown to reduce the severity of articular cartilage breakdown in various animal models of osteoarthritis (OA). This disease modifying effect is associated with reductions in the levels of active and total collagenase and gelatinase in extracts of articular cartilage from the involved joint. These observations appear to justify a clinical trial of doxycycline, a readily available, inexpensive antimicrobial that has been used therapeutically in humans with OA for years with an excellent safety record.
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PMID:Modification by oral doxycycline administration of articular cartilage breakdown in osteoarthritis. 775 22

Cartilage destruction is one of the essential features of osteoarthritis and other degenerative disease conditions of articular disease, and it may be caused by metalloproteases induced by cytokines such as interleukin-1. To search for novel chemical entities that will block the production of metalloproteases, we have utilized an in vitro system in which macrophage-conditioned medium (a source of interleukin-1) was used to stimulate rabbit articular chondrocytes in culture. Upon treatment with macrophage-conditioned medium or recombinant interleukin-1, chondrocytes synthesize and secrete collagenase, stromelysin and other proteases into the surrounding medium and fail to organize an appropriate extracellular matrix. Using this in vitro system, we have determined that a series of naphthopyran derivatives were able to block the production of neutral metalloproteases. Structural modifications of the lead compound have revealed specific requirements for activity. This class of compounds represents one of very few that are known to block the synthesis, rather than the activity, of matrix-degrading metalloproteases and thus may be beneficial in preventing the cartilage destruction associated with several degenerative diseases of the articular joint.
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PMID:Identification of a novel chemical series that blocks interleukin-1-stimulated metalloprotease activity in chondrocytes. 779 Nov 27

This study was conducted to determine the presence of immunoglobulin G (IgG) and albumin in deep layers of articular cartilage from patients with rheumatoid arthritis or osteoarthritis and from normal organ donors. Cartilage plugs were cut into 20-microns slices with a microtome and ten consecutive slices were pooled, dividing the specimen into 200 microns sections starting from the articular surface. Each pool was extracted overnight thrice with neutral buffer, thrice with 6 M guanidine hydrochloride, and then degraded with bacterial collagenase. IgG and albumin were quantified in each extract. From the surface and deep layers significantly more IgG and albumin were extracted from rheumatoid than from normal specimens, both with neutral buffer and with guanidine. In neutral buffer extracts the molar ratios of IgG to albumin were comparable from normal and rheumatoid specimens, with a molar excess of albumin. In contrast, the molar ratios of IgG to albumin in guanidine extracts from rheumatoid cartilages were significantly higher than in normal cartilages, and the IgG was in molar excess of albumin only in rheumatoid extracts. These results show for the first time that IgG has penetrated deep into the cartilage in rheumatoid arthritis and may contribute to the degradation of cartilage by inflammation.
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PMID:Deep penetration of antibodies into the articular cartilage of patients with rheumatoid arthritis. 783 77

In this study we have investigated whether direct cell to cell contact between activated paraformaldehyde-fixed T cell clones obtained from synovial tissue of patients with osteoarthritis (OA) or rheumatoid arthritis and target monocytic cells or dermal fibroblasts influenced the balance between interstitial collagenase and its specific inhibitor tissue inhibitor of metalloproteinases (TIMP) produced by the latter cell types. PHA/PMA-activated fixed T cell clones or their membranes strongly induced the production of collagenase both in monocytic THP-1 cells and in dermal fibroblasts. In contrast, only low levels of TIMP were induced in THP-1 cells and no change of TIMP expression was observed in fibroblasts as a result of stimulation with PHA/PMA-activated T cells or T cell membranes. Anti-CD3-activated T cell clones stimulated the production of collagenase both in THP-1 cells and fibroblasts, whereas TIMP levels were not influenced. Collagenase production in THP-1 cells induced by anti-CD3-activated T cell clones was 1) dependent on the dose of anti-CD3 used to stimulate the T cells, 2) initiated only when CD3 was cross-linked, and 3) inhibited when cyclosporin A was included during T cell activation. Our data collectively indicate that activated T cells in contact with monocytic cells or fibroblasts may alter the balance between interstitial collagenase and its specific inhibitor TIMP. This selective induction of a mediator profile representative of matrix breakdown as a result of target cell interaction with activated T cells may be an important factor in the local process of tissue destruction that characterizes osteoarthritis and rheumatoid arthritis.
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PMID:Immobilized anti-CD3 antibody activates T cell clones to induce the production of interstitial collagenase, but not tissue inhibitor of metalloproteinases, in monocytic THP-1 cells and dermal fibroblasts. 787 39

The objective of this study was to examine the effect of the stimulation of the immune system with Mycoplasma arthritidis superantigen (MAS) on joint inflammation and cartilage destruction. MAS was administered either alone or combined with a model of degenerative arthritis induced by intraarticular injection of collagenase enzyme. Intraperitoneal injection of MAS resulted in activation of peripheral lymphocytes in BALB/c mice, as shown by a proliferative response of splenocytes isolated from MAS-treated animals to IL-2-containing supernatant. Intraperitoneal or intra-articular administration of MAS alone at concentrations maximally activating lymphocytes had no detectable effect on joints. Intra-articular injection of collagenase resulted in some infiltration of inflammatory cells into the joints, hyperplasia and hypertrophy of synovial lining, pannus formation and surface loss of proteoglycans 7 days following the injection. At 21 days, the animals showed almost total loss of cartilage and minimal or no inflammation. Animals receiving MAS in addition to collagenase treatment showed similar changes in the joints. These data have demonstrated that activation of the immune system with MAS in vivo does not increase joint inflammation or cartilage degradation in enzymatically induced arthritis.
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PMID:Effect of Mycoplasma arthritidis superantigen on enzymatically induced arthritis in mice. 788 56

Osteoarthritis is characterized by focal cartilage destruction and marked formation of osteophytes. We have investigated the possible relationship between site specific occurrence of cartilage damage and osteophytes in the collagenase induced murine osteoarthritis model. The degree of instability of the joint correlated with the amount of cartilage loss. Moreover, cartilage damage in the medial tibial plateau correlated only strongly with the osteophyte at the medial plateau, whereas a similar, site directed trend was noted for lateral damage and lateral osteophytes. A separate study with intraarticular injection of TGF beta 1 in normal murine knee joints revealed that this factor can induce osteophytes at characteristic sites, suggesting a role of endogenous TGF beta in this phenomenon.
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PMID:Cartilage destruction and osteophytes in instability-induced murine osteoarthritis: role of TGF beta in osteophyte formation? 802 46

Cultured rabbit joint chondrocytes were exposed to diacerhein (DAR : ART 50, Negma, 10(-6) to 10(-4) M), which has proved effective and safe when given for two months for the treatment of osteoarthritis. Experiments were performed with and without 500 pg/ml human recombinant interleukin-1 to determine whether diacerhein antagonizes the effects of this monokine. Glycosaminoglycan production was measured by 35S-sulfate incorporation followed by cetylpyridinium precipitation, collagen production by 3H-proline labeling and bacterial collagenase digestion, and collagenase production by determination of the amount of 3H-collagen that underwent degradation. Incubation of chondrocytes with diacerhein for 24 hours was not associated with substantial changes in glycosaminoglycan or collagen production but substantially antagonized interleukin-1-mediated enhancement of collagenase production. With longer incubation periods (6 days) with the 10(-6) M concentration of diacerhein, production of glycosaminoglycans and collagen increased. Incubation with both diacerhein and interleukin-1 for six days partly antagonized the cytokine's inhibitory effect on glycosaminoglycan and collagen production. During these experiments, the medium's ability to break down collagen was consistently reduced by diacerhein, even in the presence of interleukin-1. These data demonstrate that diacerhein can reduce or even abolish interleukin-1-mediated enhancement of collagenase production by joint chondrocytes. This effect may lead to less erosion of cartilage in degenerative joint diseases.
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PMID:[Effect of diacerhein (ART 50) on the matrix synthesis and collagenase secretion by cultured joint chondrocytes in rabbits]. 811 55

Degenerative joint disease was induced in the knee joints of mice by intraarticular injection of two different stimuli: iodoacetate and highly purified collagenase. Proteoglycan synthesis was measured in vivo at different time points in four topographical areas of the knee joint (central and peripheral parts of the patella and central parts of the medial and lateral tibial plateaus) and was compared with histological observations of localized damage to the joint. In vitro incubation with iodoacetate had a direct effect on proteoglycan metabolism. Intra-articular injection of iodoacetate in vivo inhibited the proteoglycan synthesis in cartilage from the central part of the patella. In the peripheral part of the patella, inhibition on day 1 was followed by stimulation of synthesis on days 3-30. Proteoglycan synthesis also was inhibited in the central parts of the medial and lateral tibial plateaus. The areas with inhibited synthesis had loss of safranin O staining on histology. In vitro incubation with collagenase did not have a direct effect on the proteoglycan metabolism of intact cartilage; this led to the assumption that osteoarthritis after injection of collagenase is caused by ligamentous injury, which leads to an unstable joint. Injection of collagenase in vivo stimulated the proteoglycan synthesis in cartilage from the central and peripheral parts of the patella. In an early stage of the process, the cartilage from the tibial plateaus also was slightly stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Site-specific cartilage changes in murine degenerative knee joint disease induced by iodoacetate and collagenase. 816 88


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