β‐glucan triggers spondylarthritis and Crohn's disease–like ileitis in SKG mice

Ruutu, Merja; Thomas, Gethin; Steck, Roland; Degli-Esposti, Mariapia A.; Zinkernagel, Martin S.; Alexander, Kylie A.; Velasco, J. García; Strutton, Geoffrey; Tran, Ai; Benham, Helen; Rehaume, Linda; Wilson, Robert J.; Kikly, Kristine; Davies, Julian; Pettit, Allison R.; Brown, Matthew A.; McGuckin, Michael A.; Thomas, Ranjeny

doi:10.1002/art.34423

Cited by 228 publications

(217 citation statements)

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“…They are able to recognize and promote pathogen clearance and induce inflammatory signals. This process seems to follow the Syk and CARD9 pathway which was recently implicated in a mouse model of SpA (Ruutu et al, 2010). The upregulation of CLEC4D, observed for the first time in an expression profiling study of AS patients (Pimentel-Santos et al, 2011), supports the importance of innate immune mechanisms in AS pathology.…”

Section: Lessons From Genomic Profiling In As 21 the Link Between Ansupporting

confidence: 54%

Lessons from Genomic Profiling in AS

Pimentel-Santos

Branco

Thomas

2012

Clinical and Molecular Advances in Ankylosing Spondylitis

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Section: Lessons From Genomic Profiling In As 21 the Link Between Ansupporting

confidence: 54%

Lessons from Genomic Profiling in AS

Pimentel-Santos

Branco

Thomas

2012

Clinical and Molecular Advances in Ankylosing Spondylitis

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“…PTGER4 then induces the production of IL-23 and IL-17, promoting the expansion of Th17 lymphocytes (Figure 3). 114 It has been reported that when SKG mice are treated with β-glucan they develop spondyloarthritis and Crohn's disease, 115 and that this model is characterised by activation of Th17 cells. 116 This model suggests that involvement of the IL-23 signalling pathway in AS pathogenesis may be triggered by ubiquitous pathogens carrying β-glucan.…”

Section: -111mentioning

confidence: 99%

The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

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“…Sakaguchi et al, demonstrated that this mutation altered the threshold of thymic selection thus it increased the pool of self-reactive 27 T cells, which led to spontaneous polyarthritis and bone destruction mimicking RA [158]. [160].…”

Section: -53 Skg Mouse Modelmentioning

confidence: 99%

“…Anti-mouse IL-23 antibody and IL-17 deficiency both prevent the development of peripheral arthritis, spondylitis and ileitis [160].…”

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confidence: 99%

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

Tseng¹

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Ankylosing spondylitis (AS) is a chronic inflammatory arthritis characterised by severe inflammation of the axial skeleton followed by bone formation that can lead to ankylosis.The mechanisms mediating the transition from inflammation to bone formation are poorly understood due to the limited availability of relevant bone samples. Therefore, we used the proteoglycan-induced spondylitis (PGISp) mouse model to delineate the morphological changes during axial disease development. This mouse model develops spondylitis followed by ankylosis, mimicking the clinical progression seen in patients with AS.The first part of this project aimed to characterise the disease progression across a 43-week time-course in the PGISp mouse model. The principal assessment for analysing spinal disease was a semi-quantitative histological score that assessed joint inflammation, joint destruction (including intervertebral disc (IVD), cartilage and bone) and excessive tissue formation (peri-joint mesenchymal tissue expansion or fibrocartilage formation).Early inflammation initiated at the periphery of the IVD and was followed by varying levels of disc, cartilage and bone damage. In the advanced stages of disease, excessive tissue formation and ectopic chondrocyte expansion, ectopic bone and osteophyte formation were the key features. Abnormal tissue formation was always associated with IVD destruction, which was the result of inflammation, indicating that inflammation-derived IVD destruction is a prerequisite for induction of excessive tissue formation and the subsequent osteoproliferation.Current therapies for AS include non-steroidal anti-inflammatory drugs (NSAIDs), tumour necrosis factor (TNF) inhibitors and physiotherapy. However, these therapies aim to alleviate symptoms but cannot prevent syndesmophyte formation; hence new, more effective, therapeutic strategies are required. Genome-wide association studies have shown that AS is strongly associated with prostaglandin E2 (PGE2) receptor subtype 4 (EP4), which plays regulatory roles in both inflammation and bone formation. The involvement of EP4 in AS has not been examined. The second objective of this thesis was to examine the hypothesis that blocking EP4 can suppress disease progression by inhibiting both inflammation and bone formation. PGISp mice were prophylactically administered with ONO-AE1-329 (an EP4 agonist) or ONO-AE2-227 (an EP4 antagonist) ii for 16 weeks. Indomethacin, an NSAID, was included as a positive control of PGE2 signalling inhibitor. None of the treatments significantly altered peripheral arthritis or axial disease progression. Use of EP4 agonist or antagonist did not change bone mineral density and bone mineral content as measured by dual-energy X-ray absorptiometry. The

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β‐glucan triggers spondylarthritis and Crohn's disease–like ileitis in SKG mice

Cited by 228 publications

References 49 publications

Lessons from Genomic Profiling in AS

Lessons from Genomic Profiling in AS

The genomics and genetics of ankylosing spondylitis

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

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