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MMP Expression in Rheumatoid Inflammation

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MMP Expression in Rheumatoid Inflammation Genes and Immunity (2013) 14, 162–169 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene ORIGINAL ARTICLE MMP expression in rheumatoid inflammation: the rs11568818 polymorphism is associated with MMP-7 expression at an extra-articular site MG Kazantseva1, NA Hung2, J Highton3 and PA Hessian1 Matrix metalloproteinases (MMPs) contribute to the joint damage in rheumatoid arthritis (RA). Less is known of the involvement of MMPs at extra-articular sites of rheumatoid inflammation. We assessed the relative contribution from MMP-1, MMP-3, MMP-7 and MMP-12 to joint and extra-articular tissue destruction and inflammation by comparing gene expression in joint synovia and subcutaneous rheumatoid nodules from RA patients. Expression of MMP-1 and MMP-3 predominated in synovia, whereas MMP-12 expression was significantly higher in rheumatoid nodules. Markedly higher MMP-7 expression distinguished a subgroup of nodules that featured infiltrating monocyte/macrophage-producing MMP-7 protein. The high MMP-7 expression in nodules was associated with the single-nucleotide polymorphism (SNP) rs11568818 ( À 181A4G, MMP-7 promoter) and more active inflammation within the nodule lesions. Patients with such nodules had significantly earlier age of RA onset. Our findings indicate that the expression of MMP-1 and MMP-3 occurs relatively independent of the tissue microenvironment with substantial expression also at extra-articular sites. MMP-12 expression reflects the involvement of monocyte/macrophages in rheumatoid inflammation. Evidence for the association between the rs11568818 SNP and increased MMP-7 expression is restricted to nodules, which indicates that consequences of the MMP-7 polymorphism are likely to manifest within aspects of immune/inflammatory activity that are monocyte/macrophage-mediated. Genes and Immunity (2013) 14, 162–169; doi:10.1038/gene.2012.65; published online 24 January 2013 Keywords: matrixmetalloproteinase; inflammation; gene expression; polymorphism; MMP-7 INTRODUCTION and MMP-3 that, respectively, target collagenous and non- 11–13 Rheumatoid arthritis (RA) is a prototypic chronic, inflammatory collagen components of the extracellular matrix. Much less disease. The principal clinical feature is progressive destruction of is known of the tissue-destructive process in rheumatoid nodules joint tissue components, loss of function and disability.1 or the contribution MMPs make towards inflammation in this Destruction of extra-articular tissues may also be observed, such extra-articular lesion. The expression of MMP-2, MMP-3 and as the development of subcutaneous rheumatoid nodules. MMP-9 proteins has been noted previously in rheumatoid 14 Nodules occur in 25–30% of cases and are generally associated nodules, as part of an active granulomatous inflammation. In with more severe disease.2 other granulomas, MMP-9 and MMP-12 emerge as mediators of The subcutaneous rheumatoid nodule is a necrotising the extensive connective tissue destruction and/or tissue 15–17 granuloma that has a highly organised and uniform structure.3 remodelling. In a comparison of gene expression between The centre of the nodule comprises necrotic tissue that includes inflamed RA synovium and subcutaneous nodules, our preliminary deposits of necrotic collagen and reticulin fibres admixed data highlighted two further members of the MMP enzyme family, with fibrinoid material, cellular debris and substantial amounts of MMP-7 (matrilysin-1; PUMP-1) and MMP-12 (macrophage S100 proteins.2,4 This necrotic centre is surrounded by a ‘palisade’ elastase), both with functions that may contribute to the of monocyte/macrophages infiltrating from the vascular peri- granulomatous inflammation and tissue destruction seen in phery.3 T cells and putative dendritic cells colocalise immediately rheumatoid nodules. outside the ‘palisade’ layer and in the perivascular area.5–7 While MMP-7 is distinct among the MMP family as it lacks the plasma cells may be present, there is no significant B-lymphocyte carboxyl-terminal haemopexin-like domain common to all other component to the inflammatory infiltrate in subcutaneous members that would normally function to restrict substrate 18 nodules.8 specificity. Consequently, MMP-7 possesses potent and broad Tissue destruction is a feature of both the rheumatoid nodule proteolytic activity. MMP-7 is produced by a variety of normal and joint synovial lesions in RA.8 The irreversible destruction of cells, including glandular and mucosal epithelial cells, 18 cartilage, tendon and bone that comprise the synovial joints is keratinocytes, fibroblasts and also by monocyte/macrophages 19–21 well documented. Inflammatory cytokines, including tumour at various stages of their differentiation. 22,23 necrosis factor (TNF)-a and interleukin (IL)-1b,9,10 stimulate the MMP-12 is expressed predominantly by macrophages production of matrix metalloproteinases (MMPs), including MMP-1 and is an important modulator of macrophage trafficking during 1Department of Physiology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand; 2Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand and 3Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Correspondence: Dr PA Hessian, Department of Physiology, Otago School of Medical Sciences, University of Otago, Dunedin PO Box 913, Dunedin 9054, New Zealand. E-mail: [email protected] Received 15 June 2012; revised 22 November 2012; accepted 10 December 2012; published online 24 January 2013 Metalloproteinases in inflammation MG Kazantseva et al 163 Figure 1. Comparison of MMP gene expression in rheumatoid synovial and nodule tissues. (a) Comparisons of MMP-1, MMP-3, MMP-7 and MMP-12 gene expression in rheumatoid synovia (K; n ¼ 11) and rheumatoid nodule tissues (’; n ¼ 24). Gene expression was analysed using quantitative RT-PCR. All mRNA levels are expressed relative to GAPDH. Individual sample values are shown with the group mean±s.d. (horizontal bars); NS, not significant (P40.05); ***Po0.001 by Mann–Whitney, two-sided U-test. (b) Comparisons of MMP-7 gene expression in rheumatoid synovia (n ¼ 11) and nodule tissues with low MMP-7 (L) (n ¼ 17) or high MMP-7 (H) expression (n ¼ 7). High or low MMP-7 expression in the nodule tissue was distinguished by a nominal threshold, defined by the nodule group mean±1 s.e. NS, not significant (P40.05); **Po0.01; ***Po0.001 by Kruskal–Wallis Dunn’s multiple comparison test. Data for individual samples are shown as detailed above. inflammation, through its effect upon several matrix components, Table 1. Patient demographics including elastin and basement membrane proteins.23 Owing to the functional redundancy among MMP family Tissue specimen members, the biological relevance of an individual MMP is 24 primarily determined by its particular pattern of expression. In Nodule Synovium tissues affected by inflammation, multiple signalling pathways that involve glucocorticoids, transforming growth factor-b, TNF-a, Patients 24a 10b IL-1b, IL-6 or interferon (IFN)-g have been shown to regulate MMP Gender 20 Females 8 Females ± ± gene expression.25 Sequence variations within gene pro- Age (years) 58.8 11 57.8 14.4 Dis. duration (years) 17.2±10.8 15.0±9.4 moter regions are also associated with altered MMP gene 26–28 Nodules 24 (100%) 8 (80%) expression. For the MMP-7 promoter, both an A to G Erosions 23 (95.8%) 9 (90%) transition at the À 181-bp position ( À 181A4G; rs11568818), Rheumatoid factor 21 (87.5%) 9 (90%) and a C to T substitution at position À 153 ( À 153C4T; ACPA 14/15 (93.3%)c 7/8 (87.5%) rs11568819) have been shown to increase MMP-7 gene ESR 29.5±19.3 31.9±24.3 expression in vitro.26 Consequently, the activity of the À 181G Abbreviations: ACPA, anti-citrullinated peptide antibody; ESR, erythrocyte allele promoter region is about two- to threefold higher a 26 sedimentation rates. Unless indicated, all values are mean±s.d. Three with an associated increase in protein expression. In genetic paired synovial and nodule samples were included, obtained at the same association studies, the MMP-7 À 181A4G polymorphism time. bTwo synovial samples were from the same patient, taken B5 29–31 has been associated with increased risk of several cancers, months apart. cACPA values ware not available for all patients. coronary artery disease26 and, recently, with the degree of disability in RA.32 This study compared expression of the MMP-1, MMP-3, MMP-7 further study, we distinguished high or low MMP-7 expression and MMP-12 genes in RA synovial tissue with that in extra- as levels of gene expression above a nominal threshold (1.20 ng articular nodule lesions. Increased MMP-7 gene expression was of gene-specific RNA), defined by the nodule group mean±1s.e. found in a subgroup of rheumatoid nodules that was associated By this criterion, 7 of 24 nodules (29%) showed significantly with the À 181A4G polymorphism in the MMP-7 promoter region higher MMP-7 expression (2.73±1.73 ng RNA; mean±s.d.) when and manifest solely in nodules. This is first genotype–phenotype compared with remaining nodules with low MMP-7 expression study, which links the À 181A4G polymorphism and increased (0.14±0.19 ng RNA; Po0.001) or to levels of MMP-7 expression in MMP-7 expression in the tissue-destructive inflammatory lesions all synovial tissues (0.11±0.08; Po0.01; Figure 1b). of RA. MMP-7 ( À 181A4G) promoter polymorphism is associated with increased MMP-7 expression in rheumatoid nodules RESULTS We further investigated whether a genetic predisposition under- MMP expression in rheumatoid synovial and nodule tissues lies the increased MMP-7 expression observed in a subgroup of Expression levels of the genes MMP-1, MMP-3, MMP-7 and MMP-12 rheumatoid nodule tissues. Two functional single-nucleotide were compared in rheumatoid synovial and nodule tissues polymorphisms (SNPs), À 181A4G and À 153C4T, that occur (Table 1) using real-time polymerase chain reaction (RT–PCR) in the promoter region of the MMP-7 gene were considered.
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