Endocrine Abstracts (2002) 3 S23

Matrix metalloproteinases, cytokines and bone/cartilage remodelling

RA Maciewicz1, J Bowyer1, N Brownrigg1, L Goodwin1, R Pickford2, J Tessier2, J Waterton2 & R Westwood3

1Respiratory and Inflammation Department, AstraZeneca, Macclesfield, UK; 2Enabling Science and Technology Department, AstraZeneca, Macclesfield, UK; 3Safety Assessment Department, AstraZeneca, Macclesfield, UK.

In arthritides, such as osteoarthritis (OA), there is considerable bone and cartilage remodelling associated with the disease progression. The destruction of these tissues is responsible for the pain and disability associated with the disease. Metalloproteinases (MPs) are thought to contribute to this process but as yet this remains unproven in the clinic.

The objective of this study was to elucidate the role of the specific MPs, aggrecanase and collagenase 3, in the Dunkin Hartley guinea pig, which spontaneously develop OA-like lesions in an age dependent manner. Using in vivo 3D magnetic resonance imaging (MRI) on anaesthetised animals, we have observed longitudinal changes in bone and cartilage remodelling. These include osteophyte formation, cartilage synthesis and destruction, which were similar to that observed in humans. Histological and biochemical analysis of the knee joint supports a role for aggrecanase early in the disease process; while collagenase 3 activity correlates directly with cartilage lesion formation. This data is supported from studies using biomarkers that specifically recognise bone and cartilage degradation products generated by these two enzymes. In in vitro studies, cytokines, such as IL-1, oncostatin M and TNF, were shown to induce these enzymes and tissue destruction. Finally the role of aggrecanase and collagenase 3 in the development of OA-like lesions in the guinea pig is further supported from in vivo study of metalloproteinase inhibitors on cartilage lesion progression using MRI.

Our results provide evidence that aggrecanase and collagenase are responsible for the tissue remodelling observed in the development of OA in the guinea pig and support their role in human OA.

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