(Taken from the application): The role of collagenase-3 in the pathophysiology of osteoarthritis is becoming well-established. This enzyme cleaves collagen II (the major protein component of cartilage) with high specificity. Several studies have identified increased levels of collagenase-3 (and other matrix metalloproteinases) in arthritic synovial fluid. We have shown that osteoblasts, chondrocytes and fibroblasts can remove collagenase-3 from the surrounding milieu by binding the enzyme to a specific receptor. The enzyme is then internalized and degraded through the actions of the endocytotic receptor, the low-density lipoprotein-receptor related-protein (LRP). Such a process provides a mechanism for the controlled elimination of a potentially destructive enzyme. Further, we have demonstrated that osteoarthritic chondrocytes appear to have lesser abilities to remove this enzyme, perhaps exacerbating their production of collagenase-3 in the joint spaces. In addition, we have shown that statins can enhance the removal of collagenase-3 by osteoarthritic chondrocytes. As a result, our hypothesis is that enhancement of abundance of the LRP by treatment of osteoarthritic chondrocytes with statins provides a mechanism for controlled removal of collagenase-3 from the extracellular space of cartilage, which is functional under normal physiology. Thus, the aims of this proposal are to further characterize this process and the site of action of the statins. This will be accomplished by: i) characterizing the collagenase removal process in chondrocytes. ii) investigating the cause of the down-regulation of the collagenase removal system in osteoarthritic chondrocytes. iii) examining the effect of the statins on the collagenase removal process in osteoarthritic chondrocytes. iv) determining the mechanism of action of the statins on the collagenase removal process. This work will offer insight into the basic pathophysiology of osteoarthritis and will be the basis for a new treatment option as well as determining the mechanisms of that treatment.
| Raggatt, L J; Jefcoat Jr, S C; Choudhury, I et al. (2006) Matrix metalloproteinase-13 influences ERK signalling in articular rabbit chondrocytes. Osteoarthritis Cartilage 14:680-9 |
| Walling, H W; Raggatt, L J; Irvine, D W et al. (2003) Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis. Osteoarthritis Cartilage 11:854-63 |
| Raggatt, Liza J; Partridge, Nicola C (2002) HMG-CoA reductase inhibitors as immunomodulators: potential use in transplant rejection. Drugs 62:2185-91 |
