Pristane-induced Arthritis Model Research Articles

Functional Analysis of Autoantibody Signatures in Rheumatoid Arthritis.

For the identification of antigenic protein biomarkers for rheumatoid arthritis (RA), we conducted IgG profiling on high density protein microarrays. Plasma IgG of 96 human samples (healthy controls, osteoarthritis, seropositive and seronegative RA, n = 24 each) and time-series plasma of a pristane-induced arthritis (PIA) rat model (n = 24 total) were probed on AIT’s 16k protein microarray. To investigate the analogy of underlying disease pathways, differential reactivity analysis was conducted. A total of n = 602 differentially reactive antigens (DIRAGs) at a significance cutoff of p < 0.05 were identified between seropositive and seronegative RA for the human samples. Correlation with the clinical disease activity index revealed an inverse correlation of antibodies against self-proteins found in pathways relevant for antigen presentation and immune regulation. The PIA model showed n = 1291 significant DIRAGs within acute disease. Significant DIRAGs for (I) seropositive, (II) seronegative and (III) PIA were subjected to the Reactome pathway browser which also revealed pathways relevant for antigen presentation and immune regulation; of these, seven overlapping pathways had high significance. We therefore conclude that the PIA model reflects the biological similarities of the disease pathogenesis. Our data show that protein array analysis can elucidate biological differences and pathways relevant in disease as well be a useful additional layer of omics information.

FRI0024 Antagonizing endosomal toll-like receptors diminishes inflammatory arthritis

BackgroundRheumatoid arthritis (RA), the most common chronic inflammatory joint disease, has a definite autoimmune background. There is evidence that release of endogenous nucleic acids triggers autoimmune reactions important for the...

THU0102 The Involvement of Toll-Like Receptor 9 in the Pathogenesis of Erosive Arthritis

BackgroundToll-like receptors (TLR) such as TLR7 and TLR9 that are activated by nucleic acids are known to be involved in the pathogenesis of systemic lupus erythematosus (SLE) while their role...

A TLR 9 antagonist diminishes arthritis severity in a rat model of rheumatoid arthritis

BackgroundThere is evidence that release of endogenous nucleic acids may trigger autoimmune reactions crucially involved in the induction of systemic autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis...

The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis.

To investigate the genetic regulation of rheumatoid factor (RF) in a rat model of rheumatoid arthritis, in order to gain understanding of the enigmatic role of RF in the disease. IgM-RF and IgG-RF, as well as total levels of immunoglobulins of different subclasses, were measured in sera from rats with pristane-induced arthritis (PIA). The major gene regions were identified by linkage analysis of genetically segregating crosses. The production of RF was found to correlate with development of arthritis and to be higher in females than in males. Surprisingly, the relatively arthritis-resistant E3 strain had higher levels of RF than the arthritis-susceptible DA strain. In an (E3 x DA)F(2) cohort a major locus controlling the levels of IgM-RF in serum was identified on chromosome 11 (Rf1) and another on chromosome 16 (Rf3), and these were not related to arthritis susceptibility. However, the Rf2 locus on chromosome 4 controlled IgG-RF levels, IgG2a levels, and chronic arthritis in males (Pia5). Some previously defined arthritis loci (Pia4, Pia6, Pia7, and Pia8) were found to also control immunoglobulin levels in serum. RFs are produced in the rat PIA model and correlate with development of arthritis. Gene regions controlling RF and serum immunoglobulin levels were identified, of which some cosegregated with arthritis. This suggests a new focus of study to elucidate the role of RF in the pathogenesis of arthritis.

Genetic links between the acute-phase response and arthritis development in rats.

ObjectiveThe acute‐phase inflammatory response is closely correlated with the development of rheumatoid arthritis, but the pathophysiologic role of its specific components is largely unknown. We investigated the genetic control of the acute‐phase protein response in pristane‐induced arthritis (PIA), which is a chronic erosive arthritis model in rats.MethodsPlasma levels of the acute‐phase proteins interleukin‐6 (IL‐6), α1‐acid glycoprotein (orosomucoid), fibrinogen, and α1‐inhibitor3 were quantified in 3 strains of rats during the development and progression of disease: DA and LEW.1F, which are susceptible to arthritis, and E3, which is resistant. Genetic linkage analysis was performed on an F2 intercross between E3 and DA to determine the genetic control of the acute‐phase response in arthritis. Elevated levels of α1‐acid glycoprotein were associated with acute inflammation, whereas levels of IL‐6 were increased during the entire course of the disease.ResultsUsing these acute‐phase markers as quantitative traits in linkage analysis revealed a colocalization of loci controlling the acute‐phase response and regions previously shown to control the development of arthritis in chromosomes 10, 12, and 14. In addition, 2 loci that were not associated with arthritis were found to regulate serum levels of the acute‐phase protein Apr1 (acute‐phase response 1) at the telomeric end of chromosome 12 and Apr2 on chromosome 5.ConclusionThe PIA model in rats is a useful tool for understanding some of the pathways leading to chronic erosive arthritis. The analysis of acute‐phase proteins in PIA and its application as quantitative traits for studying the genetics of arthritis will promote the understanding of the genetic regulation of the acute‐phase response.

Amelioration of arthritis in two murine models using antibodies to oncostatin M.

Oncostatin M (OSM) is a member of the interleukin-6 cytokine family, with well-documented effects on cell growth and differentiation. OSM also has proinflammatory and cartilage degradative properties. The aim of this study was to investigate the significance of OSM in arthritis pathology using a neutralizing antibody in arthritis models. Collagen-induced arthritis (CIA) was established in male DBA/1 mice. Reverse transcriptase-polymerase chain reaction was used to detect OSM messenger RNA (mRNA) message levels in arthritic joints. Neutralizing anti-OSM antibody or control immunoglobulin was administered on days 1 and 3 after disease onset. Animals were assessed for clinical arthritis for 2 weeks, followed by a histologic analysis of paws. Pristane-induced arthritis (PIA) was produced in male CBA mice dosed with anti-OSM or control immunoglobulin immediately before disease onset. Mice with PIA were assessed for clinical arthritis over a period of 100 days. Levels of mRNA for OSM, but not GAPDH, were elevated in arthritic joints of mice with CIA compared with those of normal controls. Mice with CIA treated with anti-OSM antibody showed significant amelioration of both the clinical severity (P < 0.01) and the number of affected paws (P < 0.01) compared with control animals. Histologic analysis confirmed these clinical findings, revealing a marked reduction in cellular infiltration of synovium and cartilage damage. In the PIA model, the incidence of arthritis was 65% in the control group compared with 0% in the anti-OSM-treated animals. These results demonstrate a key role for endogenously produced OSM as a potent mediator of joint pathology, and suggest that OSM might be a potentially important, novel therapeutic target for treatment of established rheumatoid arthritis.

Amelioration of arthritis in two murine models using antibodies to Oncostatin M

Oncostatin M (OSM) is a member of the interleukin-6 cytokine family, with well-documented effects on cell growth and differentiation. OSM also has proinflammatory and cartilage degradative properties. The aim of this study was to investigate the significance of OSM in arthritis pathology using a neutralizing antibody in arthritis models.Collagen-induced arthritis (CIA) was established in male DBA/1 mice. Reverse transcriptase-polymerase chain reaction was used to detect OSM messenger RNA (mRNA) message levels in arthritic joints. Neutralizing anti-OSM antibody or control immunoglobulin was administered on days 1 and 3 after disease onset. Animals were assessed for clinical arthritis for 2 weeks, followed by a histologic analysis of paws. Pristane-induced arthritis (PIA) was produced in male CBA mice dosed with anti-OSM or control immunoglobulin immediately before disease onset. Mice with PIA were assessed for clinical arthritis over a period of 100 days.Levels of mRNA for OSM, but not GAPDH, were elevated in arthritic joints of mice with CIA compared with those of normal controls. Mice with CIA treated with anti-OSM antibody showed significant amelioration of both the clinical severity (P < 0.01) and the number of affected paws (P < 0.01) compared with control animals. Histologic analysis confirmed these clinical findings, revealing a marked reduction in cellular infiltration of synovium and cartilage damage. In the PIA model, the incidence of arthritis was 65% in the control group compared with 0% in the anti-OSM-treated animals.These results demonstrate a key role for endogenously produced OSM as a potent mediator of joint pathology, and suggest that OSM might be a potentially important, novel therapeutic target for treatment of established rheumatoid arthritis.