Genome-wide gene expression in experimental arthritis: defining new targets of chronic/destructive rheumatoid arthritis (RA)

Genome-wide expression analysis using microarrays enables us to visualize activation of complex signaling pathways in the total genome of an organism upon biological, pharmacological and toxicological stimulus or during pathological conditions. Rheumatoid Arthritis (RA) is a complex multigenic disease with yet unknown ethiology, and consequently, suitable target for genomics approach. We have used a high density DNA filter array, containing 25,142 DNA sequences, that represents a condensed mouse genome to analyze gene expression in animal models of RA. Welldefined animal models were chosen in order to investigate clear relationships between disease activity and gene expression. We have identified a number of genes whose targeted deletion or insertion results in modification of disease progression. Gene deletion of, e.g. IL-6 prevents development of sub-chronic inflammation without modifying the acute inflammation in zymosan-induced-arthritis (ZIA). Similarly, gene deletion of FcγR prevents some aspects of chronic inflammation in antigen-induced arthritis (AIA). On the other hand, adenoviral mediated gene transfer of IL-4 completely inhibits progression into the destructive phase in collagen-induced arthritis (CIA). Therefore we have analyzed gene-expression profiles in the following conditions: A) IL-6-/- vs. WT/ZIA, B) FcγR -/- vs. WT/AIA, C) AdIL-4 vs. AdC/CIA. Possible candidate genes for (sub)chronic inflammation or destructive arthritis were defined by two-parameter and cluster analysis of the expression profile. Seventy-seven common candidates, possibly involved in sub-chronic or destructive arthritis, were defined. Many of these are genes not yet inferred to be involved in inflammation. Selected ESTs were further analyzed and one candidate was cloned as a full length gene. Investigation into gene function is in progress. This approach, combining DNA array technology with cloning and functional characterization of candidate genes, proves highly effective in defining novel targets in inflammatory/autoimmune diseases such as RA.