| Articular cartilage is comprised of resident chondrocytes interspersed throughout a complicated network of molecules called the cartilage extracellular matrix (ECM). The major component of articular cartilage ECM is type II collagen, which supplies the matrix with its characteristic tensile strength. In some forms of arthritis such as osteoarthritis (OA), type II collagen is uncontrollably destroyed ultimately leading to joint dysfunction. Type II collagen, the major collagen type found in articular cartilage, may account for 95% of the total collagen content of articular cartilage. The molecules implicated in the destruction of the ECM are a family of enzymes called matrix metalloproteinases (MMPs), of which over 20 members have been identified.; In this study, the ability to use ELISA to measure metalloproteinase-dependent release of type II collagen peptides from both in vitro and in vivo rabbit models of cartilage breakdown was evaluated. The monoclonal antibodies utilized in this investigation to measure collagen degradation were previously developed in our laboratory. In addition, the in vitro model was used to assess the inhibitory potential of several MMP inhibitors. It was determined that the in vitro rabbit explant model coupled with the measurement of CII degradation peptides is amenable to high volume screening, while the in vivo Hulth-Telhag model demonstrates rapid elevation in metalloproteinase activity resulting in considerable CII peptide release. Moreover, in a small sample study, it was shown that a double antibody sandwich ELISA utilizing antibodies 14:7:D8 and 18:6:D6 can be used measure type II collagen breakdown in synovial fluids of patients suffering from either RA or OA.; In the final section of this dissertation, the clinical potential of using MMP inhibitors as therapeutic agents is discussed. The objective of this review is to describe both MMPs and TIMPs, as well as investigate the possible clinical applications of metalloproteinase inhibitors in treating diseases such as cancer and atherosclerosis. |
