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The NF‐κB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF‐κB activity is regulated by the IKK‐2 kinase during inflammatory responses. To elucidate how IKK‐2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody‐induced arthritis.ML120B, a potent, small molecule inhibitor of IKK‐2, was administered to arthritic animals, and disease activity was monitored. NF‐κB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase–polymerase chain reaction was used to evaluate gene expression in joints. Protease‐activated near‐infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF‐κB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF‐κB pathway, i.e., KC, epithelial neutrophil–activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor α, interleukin‐1β, interleukin‐6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.Our data demonstrate that IKK‐2 inhibition in the murine model of antibody‐induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis. [ABSTRACT FROM AUTHOR]