Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis

Cunnane, Gaye; FitzGerald, Oliver; Hummel, Klaus M.; Youssef, Peter; Bresnihan, Barry

doi:10.1002/1529-0131(200108)44:8<1744::aid-art309>3.0.co;2-k

Cited by 110 publications

(69 citation statements)

References 49 publications

(53 reference statements)

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“…Quantification of Rel/NF-B subunit expression is not feasible with the use of supershift assays. The immunohistologic method utilized in this study to quantify mononuclear cell populations in synovial tissue has been validated in several previous studies (2,3,14,20). The observed increase in NF-B1 expression at sites adjacent to the CPJ is consistent with the increased levels of macrophage infiltration and activation that have been previously described at the CPJ (2,3).…”

Section: Discussionsupporting

confidence: 74%

“…In the majority of patients with RA, radiographic evidence of joint damage begins to appear during the first 6-12 months after the onset of disease, and continues to progress for many years (17,18). Critical components of the pathophysiologic pathways associated with articular matrix degradation can be identified in the synovial tissue of patients with RA very early in the course of the disease (19)(20)(21). Macrophage, T lymphocyte, synoviocyte, and endothelial cell nuclei may express activated Rel/NF-B following IL-1␤ or tumor necrosis factor ␣ (TNF␣) stimulation (4).…”

Section: Discussionmentioning

confidence: 99%

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Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Benito

Murphy

et al. 2004

Arthritis & Rheumatism

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Objective. To compare the expression of the Rel/ NF-B subunits, NF-B1 (p50) and RelA (p65), in paired synovial tissue samples selected from sites adjacent to and remote from the cartilage-pannus junction (CPJ) in patients with inflammatory arthritis.Methods. Synovial tissue was selected at arthroscopy from sites adjacent to the CPJ and from the suprapatellar pouch of patients who were referred to an early arthritis clinic. Tissue samples from patients with osteoarthritis (OA) undergoing knee arthroplasty were also studied. Rel/NF-B subunit activation and expression were measured by electrophoretic mobility shift assay and supershift analyses and by immunohistochemistry.Results. Tissue samples were obtained from 10 patients with rheumatoid arthritis (RA), 7 with a seronegative arthropathy (SnA), and 6 with OA. Rel/NF-B was abundantly expressed in all samples. In both RA and SnA synovial tissue, the absolute number of NF-B1؉ cells at the CPJ was significantly higher than at non-CPJ sites (P ‫؍‬ 0.006 and P ‫؍‬ 0.02, respectively). The proportion of cells expressing NF-B1 was also significantly higher at the CPJ compared with non-CPJ sites (P ‫؍‬ 0.003 in RA, P ‫؍‬ 0.009 in SnA). The numbers of RelA؉ cells were consistently lower throughout. In RA synovial tissue, but not in SnA synovial tissue, both the absolute number and the proportion of RelA؉ cells were significantly higher at the CPJ than at non-CPJ sites (P ‫؍‬ 0.003 and P ‫؍‬ 0.01, respectively). In OA synovial tissue, the numbers of cells expressing NF-B1 and RelA were similar to those observed at the non-CPJ sites in all inflammatory tissues studied.Conclusion. In this study of early inflammatory arthritis, expression of NF-B1 in synovial tissue was highest at sites most likely to be associated with joint erosion. These observations are consistent with a critical role of NF-B1 in joint destruction, and support the rationale for specific therapeutic inhibition of NF-B in RA.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Benito

Murphy

et al. 2004

Arthritis & Rheumatism

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“…[1][2][3][4][5] MMPs are a group of zinc-and calcium-dependent proteases that contribute to tissue remodelling and repair during development, morphogenesis, inflammation, and so on. They act by specifically degrading all of the components of the extracellular matrix, which serves as a scaffold for tissue formation.…”

Section: Introductionmentioning

confidence: 99%

Influence of variations across the MMP-1 and -3 genes on the serum levels of MMP-1 and -3 and disease activity in rheumatoid arthritis

Chen

Nixon²,

Dawes³

et al. 2011

Genes Immun

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Matrix metalloproteinases (MMPs) are involved in joint destruction in rheumatoid arthritis (RA), and are strongly associated with levels of inflammation. To understand the relationship between MMP-1 and -3 variants and MMP levels in RA, we investigated the genotypic and haplotypic relationships of the MMP-1 and -3 genes with circulating levels of these MMPs. The genotypes of single-nucleotide polymorphisms (SNPs) rs1799750 (1G/2G, MMP-1 promoter), rs495366 (G/A, intergene), rs679620 (A/G, MMP-3 coding region) and rs3025058 (5A/6A, MMP-3 promoter) were determined in 430 RA patients. Each polymorphism was associated with serum levels of MMP-1 (P trend o0.0001 for each SNP), with haplotype 1G-G-A-5A associated with the highest level. The intergenic and MMP-3 SNPs were associated with MMP-1 levels independent of the MMP-1 promoter SNP. The MMP-3 SNPs were associated with serum MMP-3 level (P trend o0.0001 for each SNP), and were each associated with mean time-averaged disease activity (DAS28) in patients followed up for 2 years (P ¼ 0.003). Our findings indicate that several closely linked polymorphisms in the MMP-1-MMP-3 loci have an important role in determining the circulating levels of these MMPs in RA, and that MMP-3 polymorphism is associated with the level of disease activity over time.

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“…MMPs are a family of zinc-dependent endopeptidases that are capable of degrading all major components of the extracellular matrix. A number of studies have demonstrated that MMPs are important mediators in inflammatory and connective tissue diseases such as RA (11,12). Of considerable importance in arthritis are the gelatinase subfamily of MMPs, consisting of MMP-2 (gelatinase A) and MMP-9 (gelatinase B).…”

mentioning

confidence: 99%

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue

March

Sambrook

2007

Arthritis & Rheumatism

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Objective. To investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP-2) and MMP-9.Methods. Synovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot analysis.Results. Fibroblasts and monocytes from RA patients produced substantially more MMP-9 than did those from OA patients; however, there was no difference in MMP-2 production. The addition of recombinant APC markedly reduced MMP-9 at the gene and protein levels. In contrast, APC up-regulated and activated MMP-2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP-9 by APC was EPCR-dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF-B and MAP kinase p38, and inhibitors of NF-B or p38 reduced the production of MMP-9, suggesting that APC inhibits MMP-9 by blocking TNF, NF-B, and p38. Thus, APC acts on MMP-9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF-B and p38.Conclusion. APC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP-9, yet increase antiinflammatory MMP-2 activity.

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Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis

Cited by 110 publications

References 49 publications

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Increased synovial tissue NF‐κB1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis

Influence of variations across the MMP-1 and -3 genes on the serum levels of MMP-1 and -3 and disease activity in rheumatoid arthritis

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

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