Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis

Hayer, Silvia; Niederreiter, Birgit; Nagelreiter, Ionela-Mariana; Smolen, Josef S.; Redlich, Kurt

doi:10.1136/ard.2010.129148

Cited by 21 publications

(14 citation statements)

References 18 publications

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“…MMP3, a stromelysin, and MMP13, a collagenase, key enzymes in extracellular matrix remodelling, which have both been shown to be elevated in AS as well as animal models [34,44,45], were both strongly upregulated. The strong matrix formation response was also reflected with marked upregulation of the key bone matrix components Col1, bone sialoprotein and OCN, as well as a number of other extracellular matrix-associated genes.…”

Section: Discussionmentioning

confidence: 99%

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

et al. 2012

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IntroductionAnkylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression.MethodsPGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling.ResultsInflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated.ConclusionsThis study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

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Section: Discussionmentioning

confidence: 99%

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

et al. 2012

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“…Mice over-expressing human TNF (hTNF.Tg mice), which are characterised by focal bone erosion similar to RA, and bilateral sacroilitis associated with new bone for-mation similar to ankylosing spondylitis, have been shown to have high serum IL-6 levels (94). Genetic deletion of IL-6 expression in this model, did not modify the development of inflammation and bone formation associated with the bilateral sacroilitis, suggesting that IL-6 may not mediate these features of ankylosing spondylitis (94). However, the potential for gp130 cytokines such as OSM to downregulate the expression of Wnt signalling antagonists such as sclerostin in osteocytes (43), leaves open the possibility for gp130 cytokines to mediate the enhanced bone formation in the form of syndesmophytes in the spondylarthropathies and should be further investigated in models not dependent on TNF over-expression.…”

Section: Spondylarthropathies (Eg Ankylosing Spondylitis Psoriaticmentioning

confidence: 99%

GP130 cytokines and bone remodelling in health and disease

Sims¹,

Walsh²

2010

BMB Reports

108

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Gp130 cytokinesGlycoprotein 130 (gp130) is a receptor subunit capable of intracellular signalling that is required for the cellular action of a wide range of cytokines. The most well known of these are interleukin (IL-) 6 and IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). Every cytokine that binds to gp130 generates specific intracellular signalling events by forming specific receptor:ligand complexes, each with distinct components and/or architecture (Fig.

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“…Visvanathan et al [12] showed a correlation between the baseline IL-6 level and the MRI score and BASDAI. On the other hand, a role for IL-6 in the pathogenesis of AS was not considered crucial in a study using IL-6 knockout TNF-a transgenic mice that developed sacroiliitis [13]. Also, the correlation between AS severity and IL-6 level was not always consistent [14].…”

Section: Discussionmentioning

confidence: 97%

Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis

et al. 2011

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Ankylosing spondylitis (AS) is a chronic inflammatory osteoarticular disease. Although the etiology remains unknown, proinflammatory cytokines, such as tumor necrosis factor α and interleukin-6, have been implicated in the development of AS. Here, we report that a patient with AS, whose disease had been refractory to conventional treatment regimens and who needed to receive continuous corticosteroid, responded well to tocilizumab. While further clinical evaluation is required, tocilizumab may be an optional treatment for AS.

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Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis

Abstract: IL-6 is not a crucial regulator in an animal model of TNF-mediated bilateral, erosive sacroiliitis. This finding questions the potential of IL-6 blockade as a new treatment in patients with AS.

Cited by 21 publications

References 18 publications

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

GP130 cytokines and bone remodelling in health and disease

Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis

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