Substantial progress in understanding the pathogenesis of inflammatory arthritis has been made during the last several years. This progress has been in part due to the development of well-characterized animal models of disease. Study of animal models has allowed analysis of the disease process under controlled experimental conditions. One animal model that has the potential to further advance our knowledge is the spontaneous arthritis of mice that are deficient in the production of interleukin 1 (IL-1) receptor antagonist protein (IL-1 ra). IL-1 ra is a naturally occurring inhibitor of IL-I. It functions by occupying IL-1 receptors without transducing a signal. This model is particularly relevant because IL-1 has been shown to be critically involved in the development of joint destruction in human rheumatoid arthritis. It has been discovered, however, that not all mice are susceptible to IL-1 ra deficiency arthritis. When the deficiency was established in several strains, it was found that some were resistant and others had intermediate levels of susceptibility. BALB/c mice that are deficient in IL-1 ra develop arthritis beginning at 6 weeks of age and by 12 weeks the arthritis is fully developed with an incidence of 100%. DBA/1 mice are resistant. We propose to identify pathogenic pathways activated in BALB/c mice by gene profiling using DNA array technology. We will compare gene expression levels in wild type and IL-1 ra deficient BALB/c mice and in wild type and IL-1 radeficient DBA/1 mice. We anticipate that there will be differences in the expression profile that are associatedIL-1 ra deficiency and additional differences that are associated with the development of arthritis. BecauseIL-1 is responsible in part for the destructive phase of rheumatoid arthritis; we will also examine end organ tissues from susceptible and resistant mice for their response to IL-1 by DNA array analysis. To further establish the identity of critical pathways involved in the disease process we will analyze F2 mice generated by crossing BALB/c susceptible and DBA/1 resistant mice to identify quantitative trait loci (QTL) that are associated with either susceptibility or resistance. Comparative analysis of QTL and DNA array analysis should lead to the identification of genes responsible for either susceptibility or resistance. Selective breeding will establish the importance of particular genes in the context of either a susceptible or resistant background. These experiments will enhance our understanding of the pathways responsible for arthritis.
