Kinetic analysis of synovial signalling and gene expression in animal models of arthritis.
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.
Fukushima
Akihisa
A
Division of Rheumatology, Allergy and Immunology, University of California, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0656, USA.
Boyle
David L
DL
Corr
Maripat
M
Firestein
Gary S
GS
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4