Transcriptional profiling and pathway analysis of monosodium iodoacetate-induced experimental osteoarthritis in rats: relevance to human disease.
OBJECTIVE
The objective of this study was to characterize the rat monosodium iodoacetate (MIA)-induced model for osteoarthritis (OA) and determine the translatability of this model to human disease. This was accomplished through pathway, network and system level comparisons of transcriptional profiles generated from animal and human disease cartilage.


METHODS
An OA phenotype was induced in rat femorotibial joints following a single injection of 200mug MIA per knee joint for a period of 2 or 4 weeks. Lesion formation in the rat joints was confirmed by histology. Gene expression changes were measured using the Agilent rat whole genome microarrays. Cartilage was harvested from human knees and gene expression changes were measured using the Agilent human arrays.


RESULTS
One thousand nine hundred and forty-three oligos were differentially expressed in the MIA model, of these, approximately two-thirds were up-regulated. In contrast, of the 2130 differentially expressed oligos in human disease tissue, approximately two-thirds were down-regulated. This dramatic difference was observed throughout each level of the comparison. The total overlap of genes modulated in the same direction between rat and human was less than 4%. Matrix degradation and inflammatory genes were differentially regulated to a much greater extent in MIA than human disease tissue.


CONCLUSIONS
This study demonstrated, through multiple levels of analysis, that little transcriptional similarity exists between rat MIA and human OA derived cartilage. As disease modulatory activities for potential therapeutic agents often do not translate from animal models to human disease, this and like studies may provide a basis for understanding the discrepancies.
Barve
R A
RA
Molecular Pharmacology Group, Pfizer Global Research and Development, St. Louis, MO, USA.
Minnerly
J C
JC
Weiss
D J
DJ
Meyer
D M
DM
Aguiar
D J
DJ
Sullivan
P M
PM
Weinrich
S L
SL
Head
R D
RD
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007461:Iodoacetates / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D010003:Osteoarthritis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013223:Statistics as Topic; D014157:Transcription Factors / Q000032:analysis*; D014158:Transcription, Genetic / Q000187:drug effects*
D007461:Iodoacetates; D014157:Transcription Factors