Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synovium removed from the knee of a 10-year-old with hemophilia A was characterized morphologically and biochemically. The specimen showed villous hypertrophy with hyperplasia of synovial lining cells which contained abundant intracytoplasmic granules of hemosiderin. Monolayer cultures prepared from enzymatically dispersed tissue were characterized by pigment-laden fibroblast-like cells and round cells. Both explants of synovium and adherent cells secreted a large amount of latent collagenase and neutral proteinase into the culture medium. The secretion of these enzymes dropped sharply and intracellular pigment decreased with passage of these cultures. Lysozyme was secreted by the explants but was not detected in the monolayer culture medium. These data establish the degradative potential of the synovitis found in hemophilia and support the concept that recurrent hemarthrosis without inflammation is sufficient in and of itself to produce proliferative synovitis.
Arthritis Rheum
PMID:Proliferative synovitis in hemophilia: biochemical and morphologic observations. 62 83

There are two types of collagenases, products of two distinct genes, called MMP-1 (matrix metalloproteinase 1 or "fibroblast-type collagenase") and MMP-8 ("neutrophil collagenase"). In synovial fluid, MMP-8 is stored as latent proenzyme in polymorphonuclear neutrophils. MMP-8 is activated by hypochlorous acid produced by myeloperoxidase from hydrogen peroxide and chloride ion and by the hydroxyl radical produced in Haber Weiss reaction fed by superoxide produced by, eg, NADPH (reduced nicotinamide adenine dinucleotide) oxidase and xanthine oxidase. In addition to activation upon secretion, oxidatively modified MMP-8 is susceptible to a subsequent proteolytic attack and activation by cathepsin G. The authors suggest that activation of neutrophil-derived MMP-8 involves oxidative, nonproteolytic activation upon secretion and a more slowly progressive proteolytic activation by cathepsin G (or chymases and tryptases), and that these oxidative and proteolytic activation mechanisms act in concert. In contrast to MMP-8, MMP-1 is synthesized de novo and secreted immediately after synthesis by fibroblasts, macrophages, and some epithelial cells. Human rheumatoid synovial tissue contains mainly fibroblast-type MMP-1 collagenase as assessed by collagenase extracted from synovial tissue and by MMP-1 and MMP-8 immunostaining. It is suggested that in vivo, MMP-1 in synovitis tissue is activated by a plasminogen activator/plasminogen/prostromelysin (alternatively tryptases)/proMMP-1 cascade. In conclusion, MMP-8 and MMP-1 show type-specific compartmentalization and modes of activation in rheumatoid synovial fluid and tissue.
Semin Arthritis Rheum 1992 Aug
PMID:Collagenase in synovitis of rheumatoid arthritis. 141 81

Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) (pI approximately 9.2) into the knee joint of immunized guinea pigs and the mechanisms of articular cartilage destruction were studied morphologically and biochemically. Marked synovitis associated with polymorphonuclear leukocyte (PML) infiltration occurred within 1 day of the challenge. Articular cartilage infiltrated by PMLs was almost completely destroyed after 2 weeks. During the initial destructive process, proteoglycans were depleted from the cartilage and later collagen fibers disappeared. Granulation tissue growing in the inflamed synovium and bone marrow replaced the destroyed cartilage and joint cavity and formed fibrous scar tissue (fibrous ankylosis) by 8 weeks. Subsequently, the knee joints developed cartilagenous ankylosis by 12 weeks and finally bony ankylosis at 28 weeks. Autoradiography using 125I-aBSA and immunofluorescence studies for immunoglobulin (IgG) and complement (C3) demonstrated that the antigen is trapped in all zones of the articular cartilage and serves as a trigger for immune complex formation. Significantly increased neutral proteinase activities against substrates of proteoglycan subunits, [3H]carboxymethylated transferrin and L-pyroglutamyl-L-prolyl-L-valine-paranitroanilide were detected in homogenates of the synovium and cartilage from arthritic knee joints 1 and 2 weeks after induction. Inhibitor studies and pH curves suggested that the proteinase is leukocyte elastase. Measurable amounts of gelatinolytic activity, detected by activation with 4-aminophenylmercuric acetate and inhibited with EDTA, were also present in the same samples, but there was no detectable collagenase activity. The data on SDS-gelatin substrate gel showed that the proteinase is gelatinase derived from PMLs. These results suggest that in aBSA-induced arthritis, elastase and gelatinase from PMLs invading articular cartilage may play important roles in cartilage destruction.
 ...
PMID:Arthritis induced immunologically with cationic amidated bovine serum albumin in the guinea pig. A morphological and biochemical study on the destruction of articular cartilage. 167 78

We recently observed that specific antibodies to type II collagen do not bind in appreciable amounts to the intact surface of articular cartilage, whereas antibodies to the minor collagen types V, VI, and IX do. These results suggest that the outermost cartilage surface layer prevented interaction of the antibodies with the major collagen type in articular cartilage. The present studies were designed to investigate the pathogenic mechanisms involved in the disruption of the cartilage surface layer in inflammatory arthritis. Articular cartilage obtained from rabbits undergoing acute antigen-induced arthritis of 72 h duration showed a significant increase in binding of anti-type II antibody to cartilage surfaces compared with normal control cartilage (P less than 0.01). Augmentation of anti-type II binding was also observed upon in vitro incubation of bovine articular slices or intact rabbit patellar cartilage for 1 h with human polymorphonuclear neutrophils (PMN), PMN lysates, or purified human PMN elastase. This increase was not inhibited by sodium azide, nor was it enhanced by incubation of cartilage with the strong oxidant hypochlorous acid. Chondrocyte-mediated matrix proteoglycan degradation in cartilage explants cultured in the presence of cytokines failed to increase antibody binding appreciably. The augmentation in antibody binding seen with PMN lysates was inhibited by the nonspecific serine-esterase inhibitor PMSF, but not by the divalent metal chelator EDTA. The elastase-specific inhibitor AAPVCMK also inhibited most of the PMN-induced increase in antibody binding, whereas the cathepsin G-specific inhibitor GLPCMK was much less effective. Incubation of intact cartilage with purified human PMN elastase indicated that this serine esterase could account for the increase in anti-type II collagen antibody binding to intact cartilage surfaces. These studies suggest that in an inflammatory response, PMN-derived elastase degrades the outer layer of articular cartilage, exposing epitopes on type II collagen. They also help clarify the pathogenic mechanisms involved in early articular cartilage damage in inflammatory joint diseases.
 ...
PMID:Mechanisms of disruption of the articular cartilage surface in inflammation. Neutrophil elastase increases availability of collagen type II epitopes for binding with antibody on the surface of articular cartilage. 170 82

We studied the state of alpha 2-macroglobulin (alpha 2M), an important inhibitor of cartilage-degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive alpha 2M (i alpha 2M), which comprises alpha 2M complexed to proteinases and alpha 2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for i alpha 2M. In addition, levels of alpha 2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase-alpha 1-antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of i alpha 2M exceeded 1, indicating an intraarticular generation. Levels of i alpha 2M significantly correlated with neutrophil numbers (P less than 0.0005) and with levels of elastase-alpha 1-antitrypsin complexes and of lactoferrin (P less than 0.00001 for both). Moreover, part of i alpha 2M consisted of alpha 2M complexed to elastase-like and chymotrypsin-like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of i alpha 2M was approximately 10-fold larger than the amount complexed to these proteinases. In vitro inactivation of alpha 2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of alpha 2M, because eglin C completely abolished the inactivation of alpha 2M by cell-free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of alpha 2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of alpha 2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases.
Arthritis Rheum 1991 Sep
PMID:Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic joints. 171 87

To identify the relationship of the severity of inflammation and fibrinolytic activity in arthritis, the fibrinolytic activity of synovial fluid was studied in acute experimental arthritis induced by injecting monosodium urate crystals into dogs' knee joints. The maximum activity in the synovial fluid was observed 6 h after crystal injection. It was inferred that the fibrinolytic activity was mainly due to plasminogen activator based on fibrin plate assays, substrate specificity, inhibitor effects and zymography. On the other hand, the activity of lysosomal enzymes (beta-glucuronidase and cathepsin G) reached a peak in the synovia after 12 h. Histological examination of the synovial membrane after 12 h also showed greater inflammation than at 6 h. The peak in fibrinolytic activity preceded the peak of lysosomal enzymes and histological changes. These results suggest that an increase in fibrinolytic activity by plasminogen activator may contribute to the development of an acute inflammatory response.
 ...
PMID:Activated fibrinolytic enzymes in the synovial fluid during acute arthritis induced by urate crystal injection in dogs. 178 32

Mice with the beige mutation, which are known to be deficient for leucocyte elastase and cathepsin G, were used to investigate the role of neutral proteases in a model for antigen induced arthritis. Surprisingly, it was shown that in this model of arthritis, using methylated bovine serum albumin as an antigen, C57/black/6 'beige' mice (deficient for leucocyte neutral proteases) developed a more severe form of arthritis than the control mice ('black' mice), resulting in a higher degree of tissue damage. The incidence and degree of bone apposition and destruction of articular cartilage at day 21 after induction of arthritis were significantly higher in the beige mice. These findings could not be ascribed to differences in the cellular immune response to methylated bovine serum albumin. Autoradiographic detection of radiolabelled methylated bovine serum albumin suggested that more antigen is retained in the joints of beige mice than in black mice, which might account for the sustained arthritis and the concomitant tissue damage. These findings do not support the contention that leucocyte elastase and cathepsin G contribute to the pathogenesis of joint destruction in this model.
 ...
PMID:Antigen induced arthritis in beige (Chediak-Higashi) mice. 220 13

The contribution of neutrophil-derived elastase and cathepsin G to joint pathology has been examined in immune arthritis in the mouse. Neutrophils from beige mice are genetically deficient in lysosomal elastase and cathepsin G, but have normal levels of the acid hydrolases, beta-glucuronidase, and N-acetyl-beta-glucosaminidase. The development of antigen-induced arthritis in normal mice has been compared with that in beige mice. The pattern of synovitis (both leukocyte accumulation and plasma leakage) were indistinguishable in normal and beige mice. Cartilage proteoglycan depletion was quantified by measuring the decrease in safranin O staining intensity, and this, too, was unaltered in mice lacking elastase and cathepsin G. These results suggest that neutrophil elastase and cathepsin G do not contribute to these aspects of joint pathology in antigen-induced arthritis in the mouse.
 ...
PMID:Pathogenesis of antigen-induced arthritis in mice deficient in neutrophil elastase and cathepsin G. 224 Jan 59

We examined the effects of recombinant human tumor necrosis factor (TNF) on human articular cartilage and chondrocytes in culture. Both TNF alpha and TNF beta stimulated cartilage matrix breakdown during prolonged culture and elevated the levels of plasminogen activator (PA) activity in both the supernatants and cell layers of cultured chondrocytes. Characterization of the PA activities by immunochemistry and by zymography following gel electrophoresis indicated that human chondrocytes produce both urokinase-type PA and tissue-type PA in response to TNF. The addition of both interleukin-1 and TNF alpha or TNF beta to chondrocyte cultures demonstrated a synergism between these cytokines in the generation of PA activity in the culture supernatants and cell layers. Our results suggest that both activated lymphocytes and monocytes may contribute to the cartilage destruction of inflammatory arthritis through their stimulation of chondrocytes with TNF beta and TNF alpha, respectively. Since PA is the only neutral proteinase reported to be elevated in TNF-stimulated chondrocyte cultures, it could have an important role in TNF-mediated cartilage destruction.
Arthritis Rheum 1990 Apr
PMID:Effects of tumor necrosis factor alpha and beta on resorption of human articular cartilage and production of plasminogen activator by human articular chondrocytes. 232 32

The major low molecular weight serine proteinase inhibitor of human articular cartilage was purified to homogeneity as determined by single-peak elution with 4 high resolution techniques. The purified protein was found to be a potent inhibitor of human leukocyte elastase and cathepsin G, as well as the native serine proteinases derived from human articular cartilage and intervertebral disc. The inhibitor and lysozymes were synthesized by human articular cartilage in vitro. These properties and the ability of this cationic inhibitor to bind to cartilage matrix components suggest a possible role in the modulation of matrix catabolism in normal and pathologic states.
Arthritis Rheum 1990 Sep
PMID:Low molecular weight serine proteinase inhibitors of human articular cartilage. Isolation, characterization, and biosynthesis. 240 2


1 2 3 Next >>