Osteoarthritis (OA) is a common disabling joint disease that principally afflicts the elderly. A progressive destruction of the articular surface results from increased proteolytic activity within the cartilage. The applicant's laboratory has provided evidence of a novel proteinase, MMP proenzyme activator (MMP-PA), which activates MMP-3 (stromelysin) and MMP-9 (92k gelatinase). MMP-PA is produced by articular cartilage and may serve as an important regulator of MMP activity in this tissue in processes of development, growth and repair. The applicant's studies have also led to the discovery of serine proteinase(s) produced by cartilage that inactivate the tissue inhibitors of metalloproteinases (TIMPs). Thus, these two components, that are synthesized by cartilage, constitute an endogenous system that is likely to be a critical determinant of tissue proteolysis. The test hypothesis is that overexpression of these proteinases in OA disrupts the tight regulation of a cascade of extracellular matrix degrading enzymes, ultimately causing cartilage destruction. The goals of this proposal are the purification of MMP-PA and TIMP-cleaving proteinases, and isolation of cDNA clones. MMP-PA activates not only MMP-3 and MMP-9, but perhaps an entire degradative cascade in cartilage. Experiments are therefore proposed to determine whether MMP-PA stimulates aggrecanase-like activity in cartilage. TIMP catabolites in OA cartilage will be examined for terminal amino acid sequences consistent with in vivo action of TIMP-cleaving enzyme(s). It is suggested that by specifically inhibiting these enzymes in the cartilage of OA patients, a net gain in extracellular matrix will be created. It is further speculated that the study of serine proteinases produced by OA cartilage may have strong implications for the management of this debilitating disease.
