Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin‐1β, and joint damage in pristane‐ and collagen‐induced arthritis

Abstract

Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen- and pristane-induced arthritis (CIA and PIA). This study was undertaken to refine the Cia3 gene-containing interval toward gene identification and obtain insights into its mode of action. Five DA.F344(Cia3) subcongenic rat strains were generated and studied using the PIA and CIA models. Levels of antibodies against type II collagen (both allo- and autoantibodies) were measured. Joints and synovial tissue were collected 32 days after the induction of PIA (chronic stage) for histologic and quantitative polymerase chain reaction analysis of interleukin-1β (IL-1β) and matrix metalloproteinase (MMP) levels. Three subcongenic strains sharing the centromeric Cia3d interval were protected and 2 subcongenic strains sharing the telomeric Cia3g interval, which did not overlap with Cia3d, were also protected, developing significantly less severe CIA and PIA. Normal joint architecture was preserved in DA.F344(Cia3) and DA.F344(Cia3d) congenic rats with PIA, while DA rats had pronounced synovial hyperplasia, angiogenesis, inflammatory infiltration, and bone or cartilage erosions. The DA.F344(Cia3d) and DA.F344(Cia3g) strains had significantly lower synovial levels of IL-1β (5-fold and nearly 2-fold, respectively [the latter not reaching statistical significance]), MMP-1 (expressed predominantly in DA rats), MMP-3 (79-fold and 8-fold, respectively), and MMP-14 (21-fold and 1.4-fold, respectively) and reduced levels of pathogenic autoantibodies against type II collagen, compared with DA rats. We have identified 2 new arthritis severity and articular damage loci within Cia3. These loci regulate pathogenic processes in 2 different models of rheumatoid arthritis, and the identification of these genes has the potential to generate new targets for therapies aimed at reducing disease severity and articular damage, and may additionally have prognostic value.