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Kinetic analysis of synovial signalling and gene expression in animal models of arthritis
  1. Akihisa Fukushima,
  2. David L Boyle,
  3. Maripat Corr,
  4. Gary S Firestein
  1. Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, La Jolla, California, USA
  1. Correspondence to Professor Gary S Firestein, Division of Rheumatology, Allergy and Immunology, University of California, UCSD School of Medicine, Biomedical Science Bldg, Rm 5098, 9500 Gilman Drive, Mail code 0656, La Jolla, CA 92093-0656, USA; gfirestein{at}ucsd.edu

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.

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Footnotes

  • Funding These studies were supported, in part, by NIH grants R01AI070555, R01AI067752 and R01AR47825.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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