The goal of this grant is to evaluate the role of metalloprotease inhibitors in controlling the progression of joint diseases. In Phase I, we propose to characterize the ability of forms of TIMP to retard the breakdown of articular cartilage matrix in organ culture models of osteoarthritis. During normal physiology, the synthesis, assembly and degradation of the matrix are well coordinated events. However, in certain pathological conditions, such control well coordinated events. However, in certain pathological conditions, such control extracellular matrix breakdown is by the secretion of selective protease inhibitors called TIMPs (Tissue Inhibitors of MettaloProteinases). Several types of TIMP will be assayed for enhanced matrix protection. The inhibitory properties of these TIMP forms will be compared using two different proteases that are present in articular cartilage. The matrix protective action of the TIMPs will be determined in studies using II-1 induced bovine cartilage organ culture and naturally occurring human osteoarthritic cartilage organ culture. Evidence of enhanced matrix protection would form the basis of a Phase II application for funding of in vivo studies using animal models of osteoarthritis.
