Kinetic analysis of synovial signalling and gene expression in animal models of arthritis. Issue 5 (26th May 2009)

• Record Type: Journal Article
• Authors: Fukushima, Akihisa; Boyle, David L; Corr, Maripat; Firestein, Gary S
• Is Part Of: Annals of the rheumatic diseases. Volume 69:Issue 5(2010)
• Page Start: 918
• Page End: 923
• Publication Date: 2009-05-26
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/ard.2009.112201
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Animal models of arthritis are frequently used to evaluate novel therapeutic agents. However, their ability to predict responses in humans is variable. Objective: To examine the time course of signalling molecule and gene expression in two models of arthritis to assist with selection of the model and timing of drug administration. Methods: The passive K/BxN serum transfer and collagen-induced arthritis (CIA) models were studied. Activation of MAP kinase and interferon (IFN)-response pathways was evaluated by quantitative PCR and western blot analysis of ankle joints at various time points during the models. Results: The kinetics of gene expression and kinase phosphorylation were strikingly different in passive K/BxN and CIA. All three MAP kinases (ERK, JNK and p38) and upstream kinases were activated within days in passive K/BxN and declined as arthritis severity decreased. Surprisingly, IFN-regulated genes, including IRF7, were not induced in the model. In CIA, activation of ERK and JNK was surprisingly low and p38 phosphorylation mainly peaked late in the disease. IFN-response genes were activated during CIA, with especially prominent peaks at the onset of clinical arthritis. Conclusions: Timing of treatment and selection of CIA or passive K/BxN might have an important impact on therapeutic response. p38, in particular, increases during the late stages of CIA. ERK and JNK patterns are similar in passive K/BxN and rheumatoid arthritis (RA), while IFN-response genes in CIA and RA are similar. The dichotomy between RA and animal models could help explain the poor correlation between efficacy in RA and preclinical studies.