The long-term goal of our research is to develop an effective treatment for osteoarthritis (OA). There is no effective treatment for OA, and the potential market for an OA therapy has been estimated to be $10 billion annually. To date, efforts to develop a disease modifying drug (DMOAD) for OA have focused either on inhibiting the activity of a specific cytokine that is thought to play a pivotal role in the development of OA (e.g. IL-1), or direct inhibition of one of the several enzymes that degrade the cartilage matrix. Very little consideration has been given to agents that stimulate matrix synthesis despite the fact that such agents could slow the progressive loss of matrix and even stimulate repair of already damaged cartilage. Although a repair response is stimulated in OA joints, recent studies show that there is a localized decrease in the expression of matrix genes in regions of focal cartilage degeneration, indicating that loss of synthetic capacity is a critical element of the degenerative process. This impaired matrix synthesis cannot be explained by insufficient levels of anabolic growth factors as there is elevated expression of IGF-1 and BMP-2 in the OA joint, particularly in the lesioned areas. The more likely explanation is that the chondrocytes can no longer respond to these factors. Chondrocytes lose their ability to respond to IGF-1 with age, and human and monkey OA chondrocytes show a limited response to the anabolic effects of IGF-1. Therefore, any factor that could restore growth factor sensitivity to chondrocytes would have novel therapeutic potential for the treatment of OA. Growth factor resistance can be induced in cultured chondrocytes by IL-1 and other cytokines whose expression is elevated in the OA joint. We have identified two signal transduction inhibitors, from over 80 known inhibitors that were screened, that can completely restore the IGF-1 response to IL-1 treated chondrocytes. The primary target for these two inhibitors is the same;however, the fact that other inhibitors with the same specificity cannot restore the IGF-1 response indicates that a secondary target must be involved. Therefore, the objectives of this Phase I proposal are to a) identify this unique target using a siRNA knockdown approach, b) determine whether this target functions as a global negative modulator of IGF-1 anabolic responses and c) determine whether one of these inhibitors can stimulate repair in degenerative regions of an OA joint using a rat model of OA. PUBLIC HEALTH RELEVANCE: Currently, there is no effective treatment for osteoarthritis (OA), a severely debilitating disease that affects approximately 50% of those over 65 years of age. Our goal is to develop a novel therapeutic drug that can stimulate repair of damaged cartilage in the OA joint.