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BMC Musculoskeletal Disorders

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Open Access 01-12-2013 | Research article

Expression profiling in spondyloarthropathy synovial biopsies highlights changes in expression of inflammatory genes in conjunction with tissue remodelling genes

Authors: Gethin P Thomas, Ran Duan, Allison R Pettit, Helen Weedon, Simranpreet Kaur, Malcolm Smith, Matthew A Brown

Published in: BMC Musculoskeletal Disorders | Issue 1/2013

Abstract

Background

In the spondyloarthropathies, the underlying molecular and cellular pathways driving disease are poorly understood. By undertaking a study in knee synovial biopsies from spondyloarthropathy (SpA) and ankylosing spondylitis (AS) patients we aimed to elucidate dysregulated genes and pathways.

Methods

RNA was extracted from six SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry.

Results

Four hundred and sixteen differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, B-cell associated, matrix catabolic, and metabolic pathways. Altered "myogene" profiling was also identified. The inflammatory mediator, MMP3, was strongly upregulated (5-fold) in AS/SpA samples and the Wnt pathway inhibitors DKK3 (2.7-fold) and Kremen1 (1.5-fold) were downregulated.

Conclusions

Altered expression profiling in SpA and AS samples demonstrates that disease pathogenesis is associated with both systemic inflammation as well as local tissue alterations that may underlie tissue damaging modelling and remodelling outcomes. This supports the hypothesis that initial systemic inflammation in spondyloarthropathies transfers to and persists in the local joint environment, and might subsequently mediate changes in genes directly involved in the destructive tissue remodelling.

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Sharma S, Choi D, Planck S, Harrington C, Austin C, Lewis J, Diebel T, Martin T, Smith J, Rosenbaum J: Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles. Arthritis Res Ther. 2009, 11 (6): R168-10.1186/ar2855.CrossRefPubMedPubMedCentral

Pimentel-Santos F, Ligeiro D, Matos M, Mourao A, Costa J, Santos H, Barcelos A, Godinho F, Pinto P, Cruz M: Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects. Arthritis Res Ther. 2011, 13 (2): R57-10.1186/ar3309.CrossRefPubMedPubMedCentral

Duan R, Leo P, Bradbury L, Brown MA, Thomas G: Gene expression profiling reveals a downregulation in immune-associated genes in patients with AS. Ann Rheum Dis. 2010, 69: 1724-1729. 10.1136/ard.2009.111690.CrossRefPubMed

Gu J, Wei YL, Wei JC, Huang F, Jan MS, Centola M, Frank MB, Yu D: Identification of RGS1 as a candidate biomarker for undifferentiated spondylarthritis by genome-wide expression profiling and real-time polymerase chain reaction. Arthritis Rheum. 2009, 60 (11): 3269-3279. 10.1002/art.24968.CrossRefPubMedPubMedCentral

Smith JA, Barnes MD, Hong D, Delay ML, Inman RD, Colbert RA: Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferon-gamma dysregulation. Arthritis Rheum. 2008, 58 (6): 1640-1649. 10.1002/art.23512.CrossRefPubMedPubMedCentral

Rihl M, Baeten D, Seta N, Gu J, De Keyser F, Veys EM, Kuipers JG, Zeidler H, Yu DTY: Technical validation of cDNA based microarray as screening technique to identify candidate genes in synovial tissue biopsy specimens from patients with spondyloarthropathy. Ann Rheum Dis. 2004, 63 (5): 498-507. 10.1136/ard.2003.008052.CrossRefPubMedPubMedCentral

Rihl M, Kellner H, Kellner W, Barthel C, Yu DT, Tak PP, Zeidler H, Baeten D: Identification of interleukin-7 as a candidate disease mediator in spondylarthritis. Arthritis Rheum. 2008, 58 (11): 3430-3435. 10.1002/art.23998.CrossRefPubMed

Carron P, Van Praet L, Van den Bosch F: Peripheral manifestations in spondyloarthritis: relevance for diagnosis, classification and follow-up. Curr Opin Rheumatol. 2012, 24 (4): 370-374. 10.1097/BOR.0b013e32835448de.CrossRefPubMed

Rudwaleit M, Claudepierre P, Kron M, Kary S, Wong R, Kupper H: Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis. Arthritis Res Ther. 2010, 12 (2): R43-10.1186/ar2953.CrossRefPubMedPubMedCentral

10.

Yeremenko N, Noordenbos T, Cantaert T, van Tok M, van de Sande M, Cañete JD, Tak PP, Baeten D: Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis. Arthritis & Rheumatism. 2013, 65 (1): 174-185. 10.1002/art.37704.CrossRef

11.

Du P, Kibbe WA, Lin SM: Lumi: a pipeline for processing Illumina microarray. Bioinformatics. 2008, 24 (13): 1547-1548. 10.1093/bioinformatics/btn224.CrossRefPubMed

12.

Simon R, Lam A, Ming-Chung L, Ngan M, Menenzes S, Zhao Y: Analysis of Gene Expression Data Using BRB-Array Tools. Cancer Inform. 2007, 3: 11-17.PubMedPubMedCentral

13.

Lin SM, Du P, Huber W, Kibbe WA: Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res. 2008, 36 (2): e11-CrossRefPubMedPubMedCentral

14.

Workman C, Jensen LJ, Jarmer H, Berka R, Gautier L, Nielser HB, Saxild HH, Nielsen C, Brunak S, Knudsen S: A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol. 2002, 3 (9): research0048-CrossRefPubMedPubMedCentral

15.

Maksymowych WP, Chou CT, Russell AS: Matching prevalence of peripheral arthritis and acute anterior uveitis in individuals with ankylosing spondylitis. Ann Rheum Dis. 1995, 54 (2): 128-130. 10.1136/ard.54.2.128.CrossRefPubMedPubMedCentral

16.

Kristensen LE, Karlsson JA, Englund M, Petersson IF, Saxne T, Geborek P: Presence of peripheral arthritis and male sex predicting continuation of anti–tumor necrosis factor therapy in ankylosing spondylitis: an observational prospective cohort study from the south swedish arthritis treatment group register. Arthritis Care Res. 2010, 62 (10): 1362-1369. 10.1002/acr.20258.CrossRef

17.

Vandooren B, Tak P, Baeten D: Synovial and Mucosal Immunopathology in Spondyloarthritis. Molecular Mechanisms of Spondyloarthropathies. Edited by: López-Larrea C, Díaz-Peña R. 2009, New York: Springer, 71-84. vol. 649CrossRef

18.

D’Agostino M-A, Said-Nahal R, Hacquard-Bouder C, Brasseur J-L, Dougados M, Breban M: Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power doppler: a cross-sectional study. Arthritis & Rheumatism. 2003, 48 (2): 523-533. 10.1002/art.10812.CrossRef

19.

McGonagle D, Gibbon W, O’Connor P, Green M, Pease C, Emery P: Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis & Rheumatism. 1998, 41 (4): 694-700. 10.1002/1529-0131(199804)41:4<694::AID-ART17>3.0.CO;2-#.CrossRef

20.

Siegle I, Klein T, Backman JT, Saal JG, Nüsing RM, Fritz P: Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: Differential elevation of cyclooxygenase 2 in inflammatory joint diseases. Arthritis & Rheumatism. 1998, 41 (1): 122-129. 10.1002/1529-0131(199801)41:1<122::AID-ART15>3.0.CO;2-8.CrossRef

21.

Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Märker-Hermann E, Zeidler H, Braun J, Sieper J: Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 2012, In Press

22.

Kroon F, Landewé R, Dougados M, van der Heijde D: Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis. 2012, In Press

23.

Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, Zeidler H, Dougados M: Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005, 52 (6): 1756-1765. 10.1002/art.21054.CrossRefPubMed

24.

Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Opperman U, Dilthey A, Pirinen M, Stone MA: Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 2011, 43 (8): 761-767. 10.1038/ng.873.CrossRefPubMedPubMedCentral

25.

Zhang J, Wang JHC: Production of PGE2 increases in tendons subjected to repetitive mechanical loading and induces differentiation of tendon stem cells into non-tenocytes. J Orthop Res. 2010, 28 (2): 198-203.PubMed

26.

Chen Q, Muramoto K, Masaaki N, Ding Y, Yang H, Mackey M, Li W, Inoue Y, Ackermann K, Shirota H: A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models. Br J Pharmacol. 2010, 160 (2): 292-310. 10.1111/j.1476-5381.2010.00647.x.CrossRefPubMedPubMedCentral

27.

Chen C-H, Lin K-C, Yu DTY, Yang C, Huang F, Chen H-A, Liang T-H, Liao H-T, Tsai C-Y, Wei JCC: Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity. Rheumatology. 2006, 45 (4): 414-420. 10.1093/rheumatology/kei208.CrossRefPubMed

28.

Soliman E, Labib W, El-tantawi G, Hamimy A, Alhadidy A, Aldawoudy A: Role of matrix metalloproteinase-3 (MMP-3) and magnetic resonance imaging of sacroiliitis in assessing disease activity in ankylosing spondylitis. Rheumatol Int. 2011, 32 (6): 1-10.

29.

Kruithof E, De Rycke L, Vandooren B, De Keyser F, FitzGerald O, McInnes I, Tak PP, Bresnihan B, Veys EM, Baeten D: Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondylarthritis. Arthritis Rheum. 2006, 54 (6): 1795-1804. 10.1002/art.21914.CrossRefPubMed

30.

Yang C, Gu J, Rihl M, Baeten D, Huang F, Zhao M, Zhang H, Maksymowych WP, De Keyser F, Veys EM: Serum levels of matrix metalloproteinase 3 and macrophage colony-stimulating factor 1 correlate with disease activity in ankylosing spondylitis. Arthritis Care Res. 2004, 51 (5): 691-699. 10.1002/art.20696.CrossRef

31.

Vandooren B, Kruithof E, Yu DTY, Rihl M, Gu J, De Rycke L, Van Den Bosch F, Veys EM, De Keyser F, Baeten D: Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor α blockade in spondylarthropathy. Arthritis & Rheumatism. 2004, 50 (9): 2942-2953. 10.1002/art.20477.CrossRef

32.

Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, Haibel H, Baraliakos X, Hempfing A, Rudwaleit M: Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2009, 60 (11): 3257-3262. 10.1002/art.24888.CrossRefPubMed

33.

Haynes K, Pettit A, Duan R, Tseng H-W, Glant T, Brown M, Thomas G: Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther. 2012, 14 (6): R253-10.1186/ar4096.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/354/prepub

Title: Expression profiling in spondyloarthropathy synovial biopsies highlights changes in expression of inflammatory genes in conjunction with tissue remodelling genes
Authors: Gethin P Thomas
Ran Duan
Allison R Pettit
Helen Weedon
Simranpreet Kaur
Malcolm Smith
Matthew A Brown
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: BMC Musculoskeletal Disorders / Issue 1/2013
Electronic ISSN: 1471-2474
DOI: https://doi.org/10.1186/1471-2474-14-354

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression profiling in spondyloarthropathy synovial biopsies highlights changes in expression of inflammatory genes in conjunction with tissue remodelling genes

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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