Genetic control of experimental spondylarthropathy

Szabó, Zoltán; Szántó, Sándor; Végvári, Anikó; Szekanecz, Zoltán; Mikecz, Katalin; Glant, Tibor T.

doi:10.1002/art.21193

Cited by 17 publications

(21 citation statements)

References 46 publications

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“…Earlier we demonstrated that spondylitis susceptibility of mice of different parental strains and genetic crosses was associated with certain H-2-permissive haplotypes, which indicates the leading role of the MHC in murine arthritis and spondylitis (19). The major goal of this study was finding non-MHC genes.…”

Section: Discussionmentioning

confidence: 92%

“…Clinical symptoms, histopathological and x-ray abnormalities, and the progression of the disease in PG-immunized mice, are very similar to those in human AS. As in human patients, inflammation in mice occurs first in sacroiliac joints occupied with enthesitis, and then expands upwards involving multiple IVDs (15,19).…”

Section: Hronic Inflammation Of the Axial Skeleton And Sacroiliac Jmentioning

confidence: 90%

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Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy

Végvári

Szabó

Szántó

et al. 2005

The Journal of Immunology

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Autoimmune spondylitis was induced in BALB/c mice and their MHC-matched (BALB/c × DBA/2)F1 and F2 hybrids by systemic immunization with cartilage/intervertebral disk proteoglycan (PG). As in human ankylosing spondylitis, the MHC was the major permissive genetic locus in murine PG-induced spondylitis (PGIS). Two major non-MHC chromosome loci with highly significant linkage were found on chromosomes 2 (Pgis2) and 18 (Pgis1) accounting for 40% of the entire F2 trait variance. The dominant spondylitis-susceptibility allele for Pgis2 locus is derived from the BALB/c strain, whereas the Pgis1 recessive allele was present in the disease-resistant DBA/2 strain. The Pgis1 locus significantly affected the disease-controlling Pgis2 locus, inducing as high incidence of spondylitis in F2 hybrids as was found in the spondylitis-susceptible parent BALB/c strain. Additional disease-controlling loci with suggestive linkage were mapped to the chromosomes 12, 15, and 19. Severity of spondylitis in F2 mice positively correlated with serum levels of amyloid A, IL-6, and Pg-specific Abs, and showed negative correlation with Ag-induced T cell proliferation, IFN-γ, IL-4, and TNF-α production. A major locus controlling serum IL-6 was found on chromosome 14 near osteoclast differentiation factor Tnfsf11. Locus on chromosome 11 near the Stat3 and Stat5 genes controlled serum level of the Ig IgG2a isotype. The two major genetic loci Pgis1 and Pgis2 of murine spondylitis were homologous to chromosome regions in human genome, which control ankylosing spondylitis in human patients. Thus, this animal model of experimentally induced spondylitis might facilitate the identification of spondylitis-susceptibility genes in humans.

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Section: Discussionmentioning

confidence: 92%

Section: Hronic Inflammation Of the Axial Skeleton And Sacroiliac Jmentioning

confidence: 90%

Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy

Végvári

Szabó

Szántó

et al. 2005

The Journal of Immunology

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“…Injection of PG in dimethyldioctadecylammonium bromide (DDA), a bipolar amphiphilic micelle-forming adjuvant, accelerated the onset of PG aggrecan-induced inflammation of the spine (PGIS) to 3 to 4 weeks after the third PG-DDA injection. Susceptible animals did not need additional PG injections, but the spondylitis still developed several weeks later than the peripheral arthritis [45].…”

Section: Pg Aggrecan-induced Inflammation Of the Spine And The Jointsmentioning

confidence: 99%

“…However, this tight correlation between PGIS and PGIA can be separated when different genetic backgrounds are combined (Table 2) [45]. For instance, F1 hybrids of the BALB/c x DBA/2 intercross were fully resistant to PGIA; however, more than 30% of these (BALB/c x DBA/2)F1 mice then developed PGIS.…”

Section: Pg Aggrecan-induced Inflammation Of the Spine And The Jointsmentioning

confidence: 99%

Experimental spondyloarthropathies: Animal models of ankylosing spondylitis

Adarichev

Glant²

2006

Curr Rheumatol Rep

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Spondyloarthropathies (SpAs), including ankylosing spondylitis, are chronic inflammatory diseases of the axial skeleton. Genomic scans of SpA families revealed the overwhelming complexity of the disease, which appears to be under the control of over 20 chromosome loci, including the major SpA gene HLA-B27 within class I of the major histocompatibility complex (MHC). Animal models confirmed the primary role of MHC in SpA susceptibility and supported the hypothesis that certain enterobacterial infections can trigger SpA. Immunization of mice with proteoglycan aggrecan also can provoke SpA, thus providing the opportunity to study genetic and clinical details of the disease initiation.

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“…The genetic factors, excluding MHC-related genes, controlling axial disease were studied by crossing arthritis-susceptible BALB/c with MHC-matched arthritis-resistant DBA/2 mice [186]. Although spondylitis correlated with onset and severity of peripheral arthritis in BALB/c mice, axial disease became independent of peripheral arthritis after the F2 generation.…”

Section: -55 Il-23 Il-17 or Il-22 Overexpressionmentioning

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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Genetic control of experimental spondylarthropathy

Cited by 17 publications

References 46 publications

Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy

Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy

Experimental spondyloarthropathies: Animal models of ankylosing spondylitis

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

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