Correlation of gene and mediator expression with clinical endpoints in an acute interleukin-1beta-driven model of joint pathology.
OBJECTIVE
Interleukin-1beta (IL-1beta) plays a key role in the pathogenesis of chronic joint diseases, including osteoarthritis (OA), and drives a cascade of inflammatory and destructive responses within the synovial joint. Animal models of arthritis support the role of IL-1beta in joint pathology, however, the molecular changes downstream of IL-1beta are poorly understood in vivo. This study aimed to evaluate the intra-articular (i.a.) injection of IL-1beta in the rat joint as an acute model of joint disease and associate gene and mediator expression with clinical endpoints and pathological changes.


METHODS
The effects of i.a. administration of a pathologically relevant dose of IL-1beta on joint swelling, mechanical hyperalgesia, histopathology, gene expression and biochemical changes were measured from 2 to 24h.


RESULTS
IL-1beta-induced joint swelling and mechanical hyperalgesia. Gene expression analysis of joint tissue and biochemical analysis of joint lavage fluid identified pro-inflammatory and destructive mediators induced by IL-1beta. Histopathology of joint tissues showed evidence of synovitis and connective tissue inflammation, but not cartilage destruction. However, biochemical analysis of glucosaminoglycan levels in joint lavage fluids indicated cartilage breakdown and might be a sensitive marker of cartilage pathology.


CONCLUSIONS
Intra-articular injection of IL-1beta is a reproducible acute model of joint pathology that is potentially useful to evaluate IL-1 pathway inhibitors. The correlation of molecular events with clinical and pathological changes in this model has enhanced the understanding of the role of IL-1beta in joint disease. Methods developed for gene expression analysis using multi-gene microfluidics cards and for biochemical analysis of joint lavage fluid might have utility for characterisation of other arthritis models and corresponding human disease.
Scott
I
I
Department of Molecular Biology, AstraZeneca Charnwood, Loughborough, UK. Ian.Scott@astrazeneca.com
Midha
A
A
Rashid
U
U
Ball
S
S
Walding
A
A
Kerry
P
P
Delaney
S
S
Cruwys
S
S
D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000473:pathology*; D001169:Arthritis, Experimental / Q000235:genetics / Q000473:pathology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007270:Injections, Intra-Articular; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology*; D051381:Rats; D015203:Reproducibility of Results
D053583:Interleukin-1beta