The Arthritis Severity and Joint Damage Locus Cia25/Pia42 Is a New Genetic Regulator of the Invasive Properties of Synovial Fibroblasts

Max Brenner^1,2, Teresina Laragione^1,2 and Percio Gulko^1,2, ¹Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, ²Molecular Medicine, Hosftra North Shore-LIJ School of Medicine, Manhasset, NY

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Animal models, Autoimmunity, genetics, inflammatory arthritis and synovial cells, synovial fluid

Session Information

Title: Rheumatoid Arthritis - Animal Models I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is a chronic and commonly disabling disease with a prevalence of 1% world-wide. Disease remission is rarely achieved with current treatments and little is known about the genes that control disease severity and joint damage. We have identified the arthritis severity and joint damage regulatory quantitative trait locus, Cia25/Pia42 on rat chromosome 12, in an intercross between MHC-identical arthritis-susceptible DA and arthritis-resistant ACI rats. Cia25/Pia42 regulates collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA), two established models of RA. Cia25/Pia42 regulates the synovial expression of IL-6, IL-1β, MMP-3 and other key mediators of arthritis pathogenesis. In this study we aimed at reducing the chromosomal interval containing the gene accounting for Cia25/Pia42, and to study its effect in fibroblast-like synoviocytes (FLS).

Methods: We used genotype-guided breeding to generate twelve different DA.ACI(Cia25/Pia42) subcongenic strains. These new strains were studied in the homozygous state in PIA, and their FLS studied in an in vitroinvasion assay through Matrigel known to correlate with histologic and radiographic damage.

Results: Based on the analyses of the arthritis severity and protection in the twelve new subcongenics we were able to reduce the gene-containing interval from 23Mb to 1.7Mb. The new and reduced interval contains 34 genes. FLS from congenics had an 80% reduction in invasion, compared with DA (p=0.02).

Conclusion: We have significantly reduced the Cia25/Pia42 interval towards positional cloning, and identified evidence suggesting that at least part of its effect is mediated via FLS function and invasion. The discovery of the Cia25-Pia42 gene has the potential to generate a new target for therapy in arthritis, and a new prognostic biomarker for RA.

Disclosure:

M. Brenner,
None;

T. Laragione,
None;

P. Gulko,
None.

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