Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the mechanism of synovial damage in rheumatoid arthritis, we studied the activation of latent collagenases released from adherent rheumatoid synovial cells in culture. Latent enzyme was not complexed with alpha2 macroglobulin, the prinicpal proteinase inhibitor in serum, and could be activated by trypsin in the presence of alpha2 macroglobulin if sufficient proteinase was added to saturate inhibitor. Latent collagenase bound half as effectively to collagen fibrils as active enzyme. Plasmin was a threefold better activator of latent enzyme than trypsin and could be generated by addition of plasminogen to synovial-cell cultures. Production of both collagenase and plasminogen activator was inhibited by dexamethasone (10(-9) M). These studies emphasize in importance of control of activation in regulation collagenase activity, It is likely that rheumatoid synovium produces both latent collagenase and plasminogen activator; plasmin is activated from its zymogen, plasminogen, present in inflamed tissues, and in turn activates collagenase.
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PMID:Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator. 6 27

Immunolocalization studies of rheumatoid tissues employing specific synovial collagenase antibody have demonstrated immunoreactive enzyme at the cartilage/pannus junction. Collagenase was not detected in chondrocytes or the cartilage matrix remote from the resorbing front, and relatively little enzyme was observed in the hypertrophied synovial membrane itself. These observations directly support the idea that synovial collagenase participates in cartilage erosion in rheumatoid arthritis.
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PMID:Collagenase at sites of cartilage erosion in the rheumatoid joint. 7 Nov 52

As the proliferative lesion of rheumatoid arthritis becomes polarized and invasion of articular cartilage and subchondral bone begins, it is likely that many mesenchymal cells, including periosteal and perichondral cells, and perhaps even the chondrocytes and osteoblasts themselves can be activated to produce destructive enzymes. Early in the course of RA cartilage proteoglycans are depleted, leaving the remaining collagen more susceptible to mechanical breakdown as well as to enzymatic breakdown. Specific collagenases are released by synovial cells and, in addition, by polymorphonuclear leukocytes. The latter enzyme may account for free collagenase found in synovial fluid, a finding possibly related to saturation of inhibitory proteins by proteases with greater affinity for them, leaving collagenase active. At this time in the course of rheumatoid arthritis, a joint would be under double jeopardy from enzymes released by the invading pannus as well as by collagenase free and active in the synovial fluid. Rapid destruction could occur. Although cartilage collagen has an intrinsic resistance to collagenase conferred by its primary structure and by higher order structure (e.g. intermolecular cross-links), it seems wise to cool down hot joints because increased temperature may increase the rate of collagen degradation and, therefore, cartilage destruction. In addition, superimposed sepsis or acute flares of rheumatoid disease result in enough influx of polymorphonuclear leukocytes into the joints to result in free collagenolytic activity being present. This provides a rationale for frequent aspiration of any joint fluid, septic or otherwise, containing high polymorphonuclear leukocyte counts.
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PMID:Collagenolytic systems in rheumatoid arthritis. 16 97

Twenty-nine synovial fluids from patients with rheumatoid arthritis (RA) and 10 synovial fluids from patients with other joint diseases were investigated with regard to the presence of antibodies to denatured human collagen and of collagen-anticollagen immune complexes. 12 of the 29 RA synovial fluids showed anticollagen titres from 1:16 to 1:512 in passive haemagglutination. Only one patient in the group with no arthritis had a significant anticollagen titre of 1:32. Digestion of the synovial fluids with bacterial collagenase resulted in an anticollagen titre increase from two to four dilution steps in 9 of the RA fluids, while 6 previously negative RA synovial fluids showed anticollagen titres from 1:32 to 1:28 after digestion with collagenase. These results indicate the existence of collagen-anticollagen immune complexes in 15 of the 29 RA synovial fluids investigated.
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PMID:Demonstration of antibodies to collagen and of collagen-anticollagen immune complexes in rheumatoid arthritis synovial fluids. 18 72

In inflammatory granuloma, synovial sclerosis or inflammation and in Dupuytren's contracture, the neocollagen contains chains and/or transverse links that are characteristic of rapidly growing immature tissues. In arthrosis, a conversion of collagen synthesis towards a cutaneous type may occur. The destruction of cartilage in rheumatoid arthritis is brought about by a specific collagenase that originates from the inflamed synovial membrane. Finally, certain forms of osteoporosis may be due to alterations of the osseous collagen which impair the mechanism of calcification.
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PMID:[Biochemistry of collagen and locomotor apparatus. Hereditary diseases of the connective tissue and rheumatic diseases (3)]. 19 5

Remodelling of connective tissue and its destruction in rheumatoid arthritis is related to collagenolysis. Study of collagenase released by rheumatoid synovial cels has indicated that the enzyme is released as latent form from adherent synovial cells in culture. As a latent enzyme it is protected from complexing with alpha2 macroglobulin, the principal proteinase inhibitor. Activation in vivo is very likely caused by proteases which destroy or complex with a portion of collagenase responsible for its latency. Recent data suggest that the latent collagenase is an enzyme-inhibitor complex and not a true zymogen.
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PMID:Cellular control of collagen breakdown in rheumatoid arthritis. 20 20

Clinical and experimental data establishing a hypothesis about rheumatoid arthritis (RA) as a collagen auto-immune disease are reviewed, beginning with the demonstration of rheumatoid synovial collagenase, the demonstration of collagen antibodies in the serum and the synovial fluid of patients with RA, the demonstration of collagen inclusion bodies and collagen-anticollagen immune complexes in synovial fluid cells and the synovial fluid of patients with RA, and leading to the in vitro demonstration of the inflammatory effect of such complexes, and the induction of experimental arthritis by these complexes. Each section contains tabular summaries of various investigations. Finally, a relation between these observations and the conclusions deduced from them and the appearance of rheumatoid factors in RA and the pathogenic effect of rheumatoid factor - gammaglobulin aggregates is considered.
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PMID:[Basic studies on chronic polyarthritis as a collagen-autoimmune disease]. 21 Jun 2

Human rheumatoid arthritis (RA) collagenase and bacterial collagenase were shown to agglutinate collagen-coated erythrocytes. Native collagens of type I and type II reacted equally well, while denatured collagens showed less distinct agglutination activity. The sensitivity of the method for the detection of purified bacterial collagenase from Clostridium histolyticum is very high (100 pg). It is, however, low for human RA collagenase. The agglutination reaction is not inhibited by concentrations of native collagen causing distinct inhibition of anticollagen sera (2mg%). EDTA inhibits the agglutination completely.
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PMID:[Detection of collagenase in passive haemagglutination using collagen-coated erythrocytes (author's transl)]. 21 4

Lymphokine supernatants (LE) prepared from antigen sensitive lymphocytes caused an inhibition of migration of macrophages from capillary tubes. Control supernatants (LC) had no effect. The lymphokine supernatants, when added to macrophage cultures (the equivalent of 60 x 10(6) lymphocytes added to 40 x 10(6) macrophages), activated the macrophages so that they secreted the enzyme collagenase after 48 h and 72 h of culture. No collagenase was detected before 48 h or from macrophage supernatants to which LC was added. The macrophage supernatants (LE but not LC) also contained factors (probably enzymes) that, when added to a piece of articular cartilage in medium, caused a partial loss of the hexosamine content of the articular cartilage. These changes were seen as early as after 24 h of culture. Activated macrophages therefore release enzymes that can completely destroy cartilage. Both collagenase and a proteoglycan-hydrolyzing enzyme are released which in vivo might be responsible for the cartilage damage that is found in diseases such as rheumatoid arthritis.
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PMID:Breakdown of articular cartilage proteoglycans by lymphokine-activated macrophages. 21 34

Two patients with rheumatoid arthritis and peripheral corneal ulcerations were successfully treated by conjunctival resection. The tissues removed were assayed by a variation of the radial diffusion method for tissue collagenases. We used an agarose matrix containing lathyritic rat skin collagen. Wells 3 mm deep were punched in the agarose-collagen and surgical specimens were placed in the wells. Spaces remaining in the wells were filled with balanced salt solution. The assay dishes were incubated for four days at 32 degrees C near 100% humidity. Under these conditions release of collagenase was detected by the clearing of diffuse zones in the gel surrounding the well. Conjunctiva proximal to the ulcer produced definite zones of lysis, whereas control specimens taken remote to the ulceration produced no lysis. This direct evidence for collagenase involvement offers an exploration for the beneficial effects of conjunctival resection.
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PMID:Peripheral rheumatoid ulceration and evidence for conjunctival collagenase production. 22 Aug 78


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