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)

Four of 15 monoclonal human IgM rheumatoid factors (RF) derived from synovial B cells of patients with rheumatoid arthritis showed positive ELISA reactions with human beta 2-microglobulin. These findings were different from those previously noted using IgM RF derived from monoclonal Waldenstrom's paraproteins or the IgM components of mixed cryoglobulins, and resembled the anti-beta 2 microglobulin specificity of polyclonal IgM RF from patients with rheumatoid arthritis. Reactions of monoclonal IgM synovial RF with overlapping 7-mers of beta 2m sequence indicated major regions of positive reactivity at positions 57-64 and 89-95 which were maintained in the presence of high salt (300 mM NaCl) conditions. Glycine substitution of each residue within RF-reactive beta 2m regions indicated that tryptophanes at position 60 and 95, lysine at 58, phenylalanine at 62, valine at 93 and arginine at 97 constituted important single amino acids for the reactive epitopes. These findings indicate that clonally restricted human IgM RF derived from diseased tissues of patients with RA show anti-beta 2m reactivity similar to polyclonal RF from the same patients. This particular fine specificity is not present in monoclonal RF derived from patients with Waldenstrom's or mixed cryoglobulins showing anti-gamma-globulin activity.
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PMID:Monoclonal IgM rheumatoid factors generated from synovial B cells of rheumatoid arthritis patients react with beta 2-microglobulin. Monoclonal RF react with beta 2m. 818 Mar 16

The distribution of the matrix metalloproteinases, collagenase, stromelysin, gelatinases A and B, and the tissue inhibitor of metalloproteinases in cartilage and synovium removed from rabbits up to 27 days after induction of two models of arthritis was investigated by immunolocalization. Following intra-articular injection of poly-D-lysine/hyaluronic acid coacervate, collagenase and stromelysin were found bound to cartilage matrix, but there was little increase in chondrocyte synthesis of these enzymes. The synovium underwent a complex wound healing response involving invagination and encapsulation of the coacervate and inflammatory cell debris, during which all four metalloproteinases and tissue inhibitor of metalloproteinase could be immunolocalized. The second model, intra-articular injection of ovalbumin into sensitized rabbits, caused considerable chondrocyte necrosis; collagenase was found bound to cartilage matrix on day 13, although again there was little evidence of synthesis by chondrocytes. Inflammatory cell infiltration of meniscoid synovia took place initially, followed by fibrosis involving macrophagelike cells secreting gelatinase A. In both models there was rapid loss of glycosaminoglycan metachromasia from the cartilage matrix. These results are discussed in relation to current knowledge of metalloproteinase involvement in the chronic rheumatoid synovial pannus erosion of cartilage in humans. The data suggest that there are considerable differences between rheumatoid arthritis and these models, and their use must therefore be carefully defined.
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PMID:Rabbit models of arthritis: immunolocalization of matrix metalloproteinases and tissue inhibitor of metalloproteinase in synovium and cartilage. 834 6

Two members of the matrix metalloproteinase family of enzymes, interstitial collagenase and 92-kDa gelatinase, have been implicated in the pathogenesis of rheumatoid arthritis and tumor metastasis. In order to characterize the activities of these enzymes, we have developed a fluorogenic peptide substrate which is efficiently hydrolyzed by both enzymes. This substrate was developed based on the addition of the fluorescent tag, N-methyl-anthranilic acid (Nma), to several previously synthesized substrates that had been evaluated with respect to their turnover by interstitial collagenase. One substrate, Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys-(Nma)-NH2, had favorable solubility characteristics, was > 98% quenched, and produced a single cleavage product, Dnp-Pro-Cha-Gly, with a high fluorescence yield with both interstitial collagenase and 92-kDa gelatinase. Since the assay depends on measurement of increases in fluorescence, the position of the Nma group also proved to be important for optimization of the fluorescence signal. The assay is free from interference by organomercurial compounds and the cleavage product has excitation and emission spectra compatible with filters commonly available on commercial plate readers. The assay has been adapted to a 96-well format and provides a rapid screening protocol for the evaluation of inhibitors of these enzymes.
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PMID:A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9). 836 16

Rheumatoid arthritis (RA), one of the most common autoimmune disorders, is believed to be mediated via. T lymphocytes and genetic studies have shown that it is strongly associated with HLA-DR4. The DR4 subtypes DR4Dw4, DR4Dw14 and DR4Dw15 represent increased risk factors for RA, whereas DR4Dw10 is not associated with the disorder. Our study determines and compares the natural ligand motifs of these MHC class II molecules and identifies 60 natural ligands. At relative position 4 (P4), only the RA-associated DR4 molecules allow, or even prefer, negatively charged amino acids, but do not allow those which are positively charged (Arg, Lys). In the case of DR4Dw10 the preference for these amino acids is reversed. The results predict features of the putative RA-inducing peptide(s). A remarkable specificity, almost exclusively for negative charges (Asp, Glu), is found at P9 of the DR4Dw15 motif. This specificity can be ascribed to amino acid beta57 of the DR beta chain, and gives an important insight into the beta57-association of another autoimmune disease, insulin-dependent diabetes mellitus type I.
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PMID:Natural ligand motifs of closely related HLA-DR4 molecules predict features of rheumatoid arthritis associated peptides. 867 55

We investigated the effects of protamine on the release and the activity of 14 kDa type II phospholipase A2 (sPLA2). Protamine blocks both release and activity of sPLA2 from thrombin-stimulated platelets in a concentration-dependent manner. Heparin, an anionic sulfate polysaccharide which has a high affinity for this enzyme, has no inhibitory effect on sPLA2 by itself but it is able to reverse the inhibitory effect of protamine. The liberation by thrombin of platelet factor 4, an alpha-granule constituent, unlike to that of ATP stored in dense bodies, was suppressed by protamine. Platelet aggregation, determined in parallel, was not affected by protamine. Also, protamine did not inhibit platelet arachidonic acid liberation, which is mainly produced by cytosolic PLA2. The non-proteinaceous polycationic hexadimethrine and acidic protein casein failed to inhibit platelet sPLA2 activity. By contrast, the basic polypeptides poly(L-arginine) and poly(L-lysine) potently inhibited sPLA2 activity, indicating the important role of basic amino acids in the inhibitory effect evoked by protamine. Activities of the human recombinant sPLA2 and the unpurified synovial enzyme of patients with rheumatoid arthritis were also inhibited by the same range of protamine, poly(L-arginine) and poly(L-lysine) concentrations. Our results demonstrate that protamine, unlike heparin, blocks platelet sPLA2 release and exerts a reversible inhibitory effect on its activity, probably through the interaction of basic amino acids with the enzyme.
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PMID:Reversible inhibition by protamine of human synovial and rabbit platelet secretory phospholipase A2. 867 88

Oxidative stress is implicated in the pathogenesis of numerous disease processes including diabetes mellitus, atherosclerosis, ischaemia reperfusion injury and rheumatoid arthritis. Chemical modification of amino acids in protein during lipid peroxidation results in the formation of lipoxidation products which may serve as indicators of oxidative stress in vivo. The focus of the studies described here was initially to identify chemical modifications of protein derived exclusively from lipids in order to assess the role of lipid peroxidative damage in the pathogenesis of disease. Malondialdehye (MDA) and 4-hydroxynonenal (HNE) are well characterized oxidation products of polyunsaturated fatty acids on low-density lipoprotein (LDL) and adducts of these compounds have been detected by immunological means in atherosclerotic plaque. Thus, we first developed gas chromatography-mass spectrometry assays for the Schiff base adduct of MDA to lysine, the lysine-MDA-lysine diimine cross-link and the Michael addition product of HNE to lysine. Using these assays, we showed that the concentrations of all three compounds increased significantly in LDL during metal-catalysed oxidation in vitro. The concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine (CML) also increased during LDL oxidation, while that of its putative carbohydrate precursor the Amadori compound N epsilon-(1-deoxyfructose-1-yl)lysine did not change, demonstrating that CML is a marker of both glycoxidation and lipoxidation reactions. These results suggest that MDA and HNE adducts to lysine residues should serve as biomarkers of lipid modification resulting from lipid peroxidation reactions, while CML may serve as a biomarker of general oxidative stress resulting from both carbohydrate and lipid oxidation reactions.
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PMID:Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidation reactions. 904 7

Degradation of collagen by oxidant species may play an important role in the progression of rheumatoid arthritis. Whilst the overall effects of this process are reasonably well defined, little is known about the sites of attack, the nature of the intermediates, or the mechanism(s) of degradation. In this study electron paramagnetic resonance spectroscopy with spin trapping has been used to identify radicals formed on collagen and related materials by metal ion-H2O2 mixtures. Attack of the hydroxyl radical, from a Fe(II)-H2O2 redox couple, on collagen peptides gave signals from both side chain (.CHR'R"), and alpha-carbon[.C(R)(NH-)CO-,R = side-chain]radicals. Reaction with collagen gave both broad anisotropic signals, from high-molecular-weight protein-derived radicals, and isotropic signals from mobile species. The latter may be low-molecular-weight fragments, or mobile side-chain species; these signals are similar to those from the alpha-carbon site of peptides and the side-chain of lysine. Enzymatic digestion of the large, protein-derived, species releases similar low-molecular-weight adducts. The metal ion employed has a dramatic effect on the species observed. With Cu(I)-H2O2 or Cu(II)-H2O2 instead of Fe(II)-H2O2, evidence has been obtained for: i) altered sites of attack and fragmentation, ii) C-terminal decarboxylation, and iii) hydrogen abstraction at N-terminal alpha-carbon sites. This altered behaviour is believed to be due to the binding of copper ions to some substrates and hence site-specific damage. This has been confirmed in some cases by electron paramagnetic resonance studies of the Cu(II) ions.
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PMID:Oxidative damage to collagen and related substrates by metal ion/hydrogen peroxide systems: random attack or site-specific damage? 906 Oct 43

We describe a new principle for assessment of the activity of proteolytic enzymes of all classes and show the application of this principle for the quantitative assay of bacterial collagenase and human matrix metalloproteinases (MMPs). Central to this new principle is the presence of a proenzyme that can be activated into an active enzyme by a single proteolytic event. The regular activation sequence in the proenzyme is replaced using protein engineering by an artificial sequence recognized by the proteinase to be determined. The latter can act as an activator for the newly engineered proenzyme. In the present paper a simple colorimetric assay for the determination for MMPs is described based on this principle. With the aid of protein engineering, a modified pro-urokinase has been prepared in which the activation sequence normally recognized by plasmin (Pro-Arg-Phe-Lys upward arrowIle-Ile-Gly-Gly) has been replaced by a sequence expected to be recognized and hydrolysed by many MMPs (Arg-Pro-Leu-Gly upward arrowIle-Ile-Gly-Gly). The active urokinase resulting from activation of the modified pro-urokinase by a MMP could be measured either directly, using a specific chromogenic peptide substrate for urokinase, or indirectly via urokinase-catalysed plasminogen activation. The response of the assay to equal molar quantities of active MMPs decreases in the order MMP-2>MMP-9>MMP-1>MMP-3>MMP-7. The detection limit for MMP-9 was below 15 pM, corresponding to 3. 75x10(-15) mol per assay. Using the assay, increased MMP activity was detected in synovial tissue extracts from rheumatoid arthritis patients compared with those from osteoarthritis patients, and in stomach tumour extracts as compared with normal stomach tissue extracts.
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PMID:Modified proenzymes as artificial substrates for proteolytic enzymes: colorimetric assay of bacterial collagenase and matrix metalloproteinase activity using modified pro-urokinase. 916 91

Plasminogen (Pg) in the synovial fluid of patients with acute inflammatory disease, including rheumatoid arthritis, osteoarthritis, and gout, was purified by affinity chromatography techniques. The Pg isolated from patients with osteoarthritis and gout has affinities for L-lysine Sepharose and structural properties similar to those of normal plasma Pg. However, Pg from rheumatoid synovial fluids is abnormal in that it does not bind to L-lysine Sepharose. Analyses of rheumatoid synovial fluid Pg purified by immunoaffinity chromatography indicate that the molecule has size and folding properties similar to those of normal plasma Pg. However, we detected abnormalities in the molecule using two different criteria. First, isolated kringles 1-3 fragments are unable to bind L-lysine Sepharose. Second, reactivity toward a monoclonal antibody against a region in kringles 1-3 is decreased. In addition, rheumatoid synovial fluid Pg competes with normal plasma Pg for binding to the receptor on rheumatoid synovial fibroblasts but not on normal synovial fibroblasts. We also found that binding and activation of rheumatoid synovial fluid derived Pg on the surface of rheumatoid synovial fibroblasts elicits a rise in the concentration of cytosolic free Ca2+ similar to that of normal plasma Pg. Our data suggest that the inability of rheumatoid synovial fluid Pg to bind to L-lysine Sepharose is due to minor structural changes in kringle 1-3. These changes do not affect the physiological properties or the binding ability of synovial fluid Pg to cellular receptors on cells obtained from rheumatoid synovial tissue.
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PMID:Molecular abnormalities of human plasminogen isolated from synovial fluid of rheumatoid arthritis patients. 918 80

Dipeptidyl peptidase IV (DP IV, CD26) is a serine exoprotease which selectively cleaves the penultimate proline residue of polypeptides. This enzyme is also expressed as a surface marker on activated T cells. In order to assess the relevance of DP IV in immunological disorders, we evaluated the in vivo effects of specific DP IV inhibitors using two arthritis models, one which was induced by collagen one by alkyldiamine. These animal models share several pathological features associated with rheumatoid arthritis. The transition state substrate analog of DP IV, (S)-Alanylpyrrolidine-boronic Acid (Ala-boroPro), suppressed hind paw swelling, which was associated with collagen-induced and alkyldiamine-induced arthritis. A competitive inhibitor of DP IV, Lys(Z(NO2))-thiazolidide and an irreversible inhibitor, Ala-Pro-nitrobenzoylhydroxylamine also suppressed alkyldiamine-induced arthritis dose-dependently. We also analyzed the pharmacological effects of Lys(Z(NO2))-thiazolidide on several immune responses in vitro, in order to determine its mode of action. This inhibitor suppressed mitogen-induced and antigen-induced proliferation of T cells. However, studies using splenic cells from DP IV deficient rats showed that the inhibition of lymphocyte proliferation was not exerted through the inhibition of DP IV.
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PMID:Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV. 922 75


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