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)

Matrix metalloproteinases (MMPs) as a family of zinc-dependent endopeptidases have been involved in remodeling the extracellular matrix (ECM) in rheumatoid arthritis (RA). In RA patients synovial fluid and serum include enhanced levels of MMP-3. The 5A/6A polymorphism in the MMP-3 gene promoter can contribute to the severity of RA on account of a higher promoter activity of the 5A allele in vitro. The aim of the study was to associate the 5A/6A polymorphism of the MMP-3 gene with radiographic progression of RA. A total of 128 RA patients according to the ACR criteria were available for the study. Radiographs of both hands, obtained from all RA patients, were scored using the modified Sharp/van der Heijde method and the Steinbrocker method. The total Sharp score (TSS) and the annual radiographic progression rate (TSS/year) were calculated. Significant association with the 5A/6A polymorphism was found between patients with TSS/year <or= 1.00 and those with TSS/year > 1.00 in allelic frequencies (Pa = 0.046) and also in genotype distribution (Pg = 0.04). Compared to other genotypes the prevalence of 5A/5A genotype was lower within patients with TSS/year <or= 1.00 (odds ratio [OR] = 0.2; 95% confidence interval [CI] 0.04-0.85; P = 0.01). Also, in comparison to genotypes 5A/6A and 5A/5A, the prevalence of 6A/6A genotype was higher within patients with nonerosive RA (OR = 2.65; 95% CI 1.03-6.83, P = 0.02). Results obtained in this study provide the evidence of an association of the 5A/6A promoter polymorphism of the MMP-3 gene to the radiographic progression of RA.
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PMID:Association of the 5A/6A promoter polymorphism of the MMP-3 gene with the radiographic progression of rheumatoid arthritis. 1791 32

Matrix metalloproteinases (MMPs) are the proteases responsible for the destruction of cartilage in rheumatoid arthritis (RA) patients; especially the role of MMP-3 in RA has been highlighted from both pathophysiological studies and clinical studies. However, the role of serum MMP-3 in a large observational cohort of RA patients has not been well demonstrated. In a large observational cohort of RA patients in our Institute (IORRA, October 2000-October 2005, n=3834-5049/phase), disease activity and functional status were routinely assessed biannually. In October 2001, serum MMP-3 was measured in 1265 patients in this cohort, and the data of these patients in the subsequent 4 years were analyzed. The functional status of disability was assessed by JHAQ, the verified Japanese version of HAQ. A cut-off point of 121.0 ng/ml (men) and 59.7 ng/ml (women) was used for MMP-3 positive/negative categorization. The baseline data of these 1265 patients include 81.5% women, mean age 57.9, mean duration 11.1 years, and 71.7% of patients were rheumatoid factor (RF)-positive. Serum MMP-3 levels at the baseline (195.1+227.9 ng/ml) were weakly correlated with C-reactive protein (CRP), but qualitative elevation of serum MMP-3 using cut-off points correlated significantly with corticosteroids use, DAS28, CRP, erythrocyte sedimentation rate, JHAQ, or other markers for the disease activity, but not with age or the disease duration. Thus, elevation of serum MMP-3 level represents the disease activity of RA patients regardless of age or the disease duration. In the longitudinal analysis, the slope of JHAQ progression in patients with MMP-3 positive and RF positive, MMP-3 positive and RF negative, MMP-3 negative and RF positive and MMP-3 negative and RF negative were 0.0179, 0.0162, 0.0156, and 0.0119, respectively, indicating that JHAQ increased most progressively in RA patients with MMP-3 positive and RF positive patients, although statistically apparent differences were not identified. In 502 female patients without talking corticosteroid, patients with MMP-3 positive and RF positive were statistically more progressive in the disability than patients with MMP-3 negative and RF negative. In conclusion, elevation of serum MMP-3 in RA patients is an indicator of inflammation, and together with RF, elevation of serum MMP-3 is a predictive marker for the progression in disability especially in female patients without corticosteroid.
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PMID:Elevation of serum matrix metalloproteinase-3 as a predictive marker for the long-term disability of rheumatoid arthritis patients in a prospective observational cohort IORRA. 1792 33

Macrophage metalloelastase or matrix metalloproteinase-12 (MMP-12) appears to exacerbate atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease. An inactivating E219A mutation, validated by crystallography and NMR spectra, prevents autolysis of MMP-12 and allows us to determine its NMR structure without an inhibitor. The structural ensemble of the catalytic domain without an inhibitor is based on 2813 nuclear Overhauser effects (NOEs) and has an average RMSD to the mean structure of 0.25 A for the backbone and 0.61 A for all heavy atoms for residues Trp109-Gly263. Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly more deeply recessed under the beta-sheet. This opens a pocket between hB and beta-strand IV in the active-site cleft. Both hB and an internal cavity are shifted toward beta-strand I, beta-strand III, and helix A on the back side of the protease. About 25 internal NOE contacts distinguish the inhibitor-free solution structure and indicate hB's greater depth and proximity to the sheet and helix A. Line broadening and multiplicity of amide proton NMR peaks from hB are consistent with hB undergoing a slow conformational exchange among subtly different environments. Inhibitor-binding-induced perturbations of the NMR spectra of MMP-1 and MMP-3 map to similar locations across MMP-12 and encompass the internal conformational adjustments. Evolutionary trace analysis suggests a functionally important network of residues that encompasses most of the locations adjusting in conformation, including 18 residues with NOE contacts unique to inhibitor-free MMP-12. The conformational change, sequence analysis, and inhibitor perturbations of NMR spectra agree on the network they identify between structural scaffold and the active site of MMPs.
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PMID:Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment. 1799 11

The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-kappaB (NF-kappaB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1beta-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 microM but not 100 nM of celecoxib. The inhibitors of NF-kappaB, JNK and p38, but not ERK, decreased IL-1beta-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-kappaB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-kappaB and JNK MAPK.
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PMID:Celecoxib inhibits production of MMP and NO via down-regulation of NF-kappaB and JNK in a PGE2 independent manner in human articular chondrocytes. 1808 Jan 23

A comparative in vitro survey of physiologically relevant human and microbial proteinases defined a number of enzymes that induced specific hinge domain cleavage in human IgG1. Several of these proteinases have been associated with tumor growth, inflammation, and infection. A majority of the identified proteinases converted IgG to F(ab')(2), and a consistent feature of their action was a transient accumulation of a single-cleaved intermediate (scIgG). The scIgG resulted from the relatively rapid cleavage of the first hinge domain heavy chain, followed by a slower cleavage of the second chain to separate the Fc domain from F(ab')(2). Major sites of enzymatic cleavage were identified or confirmed from the mass of the F(ab')(2) or Fab fragments and/or the amino-terminal amino acid sequence of the Fc for each enzyme including human matrix metalloproteinases (MMPs) 3 and 12, human cathepsin G, human neutrophil elastase (Fab), staphylococcal glutamyl endopeptidase I and streptococcal immunoglobulin-degrading enzyme (IdeS). The cleavage sites in IgG1 by MMP-3, cathepsin G and IdeS were used to guide the synthesis of peptide analogs containing the corresponding carboxy-termini to be used as immunogens in rabbits. Rabbit antibodies were successfully generated that showed selective binding to different human F(ab')(2)s and other hinge-cleavage fragments, but not to intact IgG. In Western blotting studies of synovial fluids from individuals with rheumatoid arthritis, the rabbit antibodies yielded patterns consistent with the presence of endogenous IgG fragments including F(ab')(2) and the single-cleaved IgG intermediate. The detection in synovial fluid of IgG fragments similar to those observed in the in vitro biochemical studies suggests that proteolysis of IgG may contribute to localized immune dysfunction in inflammatory environments.
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PMID:Proteolysis of purified IgGs by human and bacterial enzymes in vitro and the detection of specific proteolytic fragments of endogenous IgG in rheumatoid synovial fluid. 1815 32

Elevated expression of matrix-metalloproteinases (MMP) contributes to cartilage destruction in rheumatoid arthritis. We report on a novel pathway of inflammatory activation of synovial fibroblasts that is induced by TGF-beta and laminin (extracellular matrix) and leads to increased expression of the proteases MMP-3 and MMP-10. Neither costimulation by the central inflammatory cytokines TNF-alpha and IL-1beta nor NFkB signalling is needed for this pathway.
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PMID:[Laminin-dependent inflammatory response in synovial fibroblasts of rheumatoid arthritis patients]. 1821 99

Rheumatoid arthritis (RA) synovial fibroblasts produce matrix metaloproteinases (MMPs), which destroy cartilage and bone in RA joint. Tumor necrosis factor-alpha (TNF-alpha) is one of the most important mediator leading to MMP production in RA synovial fibroblasts. Here we show that epigallocatechin-3-Gallate (EGCG) suppresses TNF-alpha-induced production of MMP-1 and MMP-3 in RA synovial fibroblasts, which was accompanied by inhibition of mitogen activated protein kinase (MAPK) and activator protein-1 (AP-1) pathways. EGCG treatment resulted in dose-dependent inhibition of TNF-alpha-induced production of MMP-1 and MMP-3 at the protein and mRNA levels in RA synovial fibroblast. EGCG treatment also inhibited TNF-alpha-induced phosphorylation of MAPKs, such as ERK1/2, p38, JNK. Electrophoretic mobility shift assay revealed that EGCG inhibits binding of AP-1 proteins to its response elements in synovial fibroblast treated. Thus, EGCG may play a role in regulating inflammation and bone destruction in RA patients.
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PMID:Epigallocatechin-3-gallate suppresses TNF-alpha -induced production of MMP-1 and -3 in rheumatoid arthritis synovial fibroblasts. 1849 96

The objective of this article was to investigate the role and expression of a novel adipocytokine, angiopoietin-like-4 (ANGPTL4), in arthropathy. Human chondrocytes were obtained from articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), who underwent total knee or hip arthroplasty. Isolated chondrocytes were cultured under hypoxic (95% N(2), 5% CO(2)) or normoxic conditions. The effects of hypoxia on ANGPTL4 expression were determined by real-time reverse transcription polymerase chain reaction and Western blot analysis. We examined the role of ANGPTL4 using small interference RNA or by stimulating chondrocytes with recombinant ANGPTL4 protein. ANGPTL4 expression in the articular cartilage specimens was examined by immunohistochemistry. Hypoxia induced a significant increase in ANGPTL4 production (p < 0.05). Incubation of chondrocytes in vitro with recombinant ANGPTL4 enhanced the expression of matrix metalloproteinase (MMP)-1 and MMP-3. Downregulation of ANGPTL4 mRNA expression by siRNA diminished the expression of MMP-1, but not that of MMP-3, suggesting that each proteinase has a distinct response to ANGPTL4. Although the in vitro responses of chondrocytes to hypoxia were similar between RA and OA samples, the in vivo expression of ANGPTL4 had unique disease-specific patterns, suggesting differences in oxygen tension in vivo. Human chondrocytes expressed ANGPTL4 and the expression was enhanced by hypoxia. ANGPTL4 might modulate cartilage metabolism by regulating MMPs.
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PMID:Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation. 1863 15

The present study aimed at characterizing the phenotype and functions of adherent synovial fluid (SF) cells derived from rheumatoid arthritis (RA), comparing with fibroblast-like synoviocytes (FLS) derived from RA synovial tissue (ST). Adherent SF-derived cells were spindle-shaped from passages 1-6 under light microscopy. The cell surface marker profile in SF-derived cells from passage 1-6 was similar to that of ST-derived FLS. Levels of MMP-1 and MMP-3 were not significantly different between SF-derived cells and ST-derived FLS (p = 0.20 and p = 0.40, respectively). There was no significant difference in the optical density value between two cell types in the cell invasion assay (p = 0.10). SF-derived adherent cells have a fibroblast-like phenotype from very early culture passages and have the potential to produce MMPs with the invasive capacity to degrade cartilage, identical to ST-derived FLS. Therefore, these cells could substitute for ST-derived FLS in studying the pathogenesis of RA.
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PMID:Phenotypic characterization and invasive properties of synovial fluid-derived adherent cells in rheumatoid arthritis. 1885 Feb 60

The IL-1beta-NF-kappaB axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1beta-induced toxicity by an overexpressing IkappaB super-repressor. Infection of FLS with Ad-IkappaB alpha (S32A, S36A), an adenovirus-containing mutant IkappaB alpha, inhibited IL-1beta-induced nuclear translocation and DNA binding of NF-kappaB. In addition, Ad-IkappaB alpha (S32A, S36A) prevented IL-1beta-induced inflammatory responses; namely, the production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3. Finally, increased cellular proliferation of FLS after IL-1beta treatment was significantly reduced by Ad-IkappaB alpha (S32A, S36A). However, Ad-IkappaB beta (S19A, S23A), the IkappaB beta mutant, was not effective in preventing IL-1beta toxicity. These results suggest that inhibition of IkappaB alpha degradation is a potential target for the prevention of joint destruction in patients with RA.
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PMID:Inhibition of IL-1beta-mediated inflammatory responses by the IkappaB alpha super-repressor in human fibroblast-like synoviocytes. 1900 49


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