Modulation of multiple experimental arthritis models by collagen‐induced arthritis quantitative trait loci isolated in congenic rat lines: Different effects of non–major histocompatibility complex quantitative trait loci in males and females

Remmers, Elaine F.; Joe, Bina; Griffiths, Marie; Dobbins, David E.; Dracheva, Svetlana; Hashiramoto, Akira; Furuya, Takefumi; Salstrom, Jennifer L.; Wang, Jianping; Gulko, Pércío S.; Cannon, Grant W.; Wilder, Ronald L.

doi:10.1002/art.10439

Cited by 64 publications

(74 citation statements)

References 35 publications

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“…Eight-to 12-wk-old rats received 150 l of pristane (2,6,10,14-tetramethylpentadecane; Sigma-Aldrich) by intradermal injection (day 0) (33,39). The dose was divided between two injection sites at the base of the tail.…”

Section: Induction Of Piamentioning

confidence: 99%

“…Based on our previous observation of gender differences in the genetic regulation of CIA (32,33), males and females were studied separately for their susceptibility to and severity of arthritis. Non-normally distributed data (medians) were compared with ANOVA on ranks with a pairwise multiple comparison procedure (Dunn's method) for multiple groups, or with the Mann-Whitney rank sum test for two group comparisons.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…To localize and to narrow the intervals containing the two arthritis-regulatory genes, and to comprehensively characterize their regulatory effects in arthritis severity, joint histology, and synovial tissue cytokine gene expression, Cia5 subcongenics were generated and studied for their susceptibility to and severity of pristaneinduced arthritis (PIA) and CIA, two well-established models of autoimmune erosive arthritis that share certain similarities in their pathogenesis and genetic regulation, but also have differences (23,25,33,39,40). We determined that Cia5 contains three different QTLs that regulate arthritis severity.…”

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confidence: 99%

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The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

Meng

Yarlett

Joe

et al. 2005

The Journal of Immunology

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Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models. A second arthritis severity locus (Cia5d) was identified within the most centromeric portion of Cia5. DA.F344(Cia5d) rats had a significantly lower median arthritis severity index in PIA, but not in CIA, compared with DA. On histologic analyses DA.F344(Cia5a) and DA.F344(Cia5d) congenics with PIA preserved a nearly normal joint architecture compared with DA, including significant reduction in synovial hyperplasia, pannus, angiogenesis, inflammatory infiltration, bone and cartilage erosions. Cia5 and Cia5a synovial levels of IL-1β mRNA were reduced. Although both DA.F344(Cia5) and DA.F344(Cia5a) rats were protected in CIA, the arthritis scores of DA.F344(Cia5) were significantly higher than those of DA.F344(Cia5a), suggesting the existence of a third locus where F344-derived alleles centromeric from Cia5a contribute to increased arthritis severity. The existence of the third locus was further supported by higher levels of autoantibodies against rat type II collagen in DA.F344(Cia5) congenics compared with DA.F344(Cia5a). Our results determined that Cia5 contains three major arthritis severity regulatory loci regulating central events in the pathogenesis of arthritis, and differentially influencing CIA and PIA. These loci are syntenic to regions on human chromosomes 17q and 5q implicated in the susceptibility to rheumatoid arthritis, suggesting that the identification of these genes will be relevant to human disease.

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Section: Induction Of Piamentioning

confidence: 99%

Section: Statistical Analysesmentioning

confidence: 99%

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The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

Meng

Yarlett

Joe

et al. 2005

The Journal of Immunology

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“…These findings stress the importance of using several models to study the regulation of arthritis by the QTLs of interest, since information concerning the function of the underlying genes may be identified. This would be especially important in studies of arthritis in rats, in which both antigen-induced and adjuvant-induced disease (PIA or oil-induced arthritis) can be investigated (40).…”

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confidence: 99%

A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

Olofsson¹,

Lu²,

Holmberg³

et al. 2003

Arthritis & Rheumatism

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Objective. To compare the genetic regulation of collagen-induced arthritis (CIA) with that of pristaneinduced arthritis (PIA) in rats.Methods. A genome-wide linkage analysis of an (E3 ؋ DA)DA backcross of rats with CIA (n ‫؍‬ 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA.Results. We found a striking, although not complete, similarity of the arthritis-controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute-phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity.Conclusion. The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA.

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“…24 Similar gender specific effects have been detected in rat and mouse intercrosses or congenic strains. 33,57,80 Sex chromosomes have also been implicated in the regulation of autoimmune arthritis. The Yaa locus in mice unexpectedly reduced CIA severity.…”

Section: Gender-gene Interactionsmentioning

confidence: 99%

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

Gulko

2007

Genes Immun

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Rheumatoid arthritis (RA) is a chronic and potentially debilitating autoimmune disease. While novel therapies have emerged in recent years, disease remission is rarely achieved. RA is a complex trait, and the identifying of its susceptibility and severity genes has been anticipated to generate new targets for therapeutic intervention. However, finding those genes and understanding their function has been a challenging task. Studies in rodent intercrosses and congenics generated from inbred strains have been an important complementary strategy to identify arthritis genes, and understand how they operate to regulate disease. Furthermore, these new rodent arthritis genes will be new targets for therapeutic interventions, and will identify new candidate genes or candidate pathways for association studies in RA. In this review-opinion article I discuss RA genetics, difficulties involved in gene identification, and how rodent models can facilitate (1) the discovery of both arthritis susceptibility and severity genes, (2) studies of gene-environment interactions, (3) studies of gene-gender interactions, (4) epistasis, (5) functional characterization of the specific genes, (6) development of novel therapies and (7) how the information generated from rodent studies will be useful to understanding and potentially treating RA.

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Modulation of multiple experimental arthritis models by collagen‐induced arthritis quantitative trait loci isolated in congenic rat lines: Different effects of non–major histocompatibility complex quantitative trait loci in males and females

Cited by 64 publications

References 35 publications

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

The Non-MHC Quantitative Trait LocusCia5Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis

A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis

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