Moderate exercise and weight loss are key components of OA care because they reduce OA pain and improve function with minimal side effects. However, many older adults are unable to maintain weight loss or regularly participate in exercise programs. Pharmacologic treatments to manage knee OA pain (e.g., opioids and non-steroidal anti-inflammatory drugs) are not strongly recommended because they have limited long-term efficacy with adverse side effects. Therefore, there is an urgent need to develop safer drug targets for managing OA pain. We are working to understand the cellular and molecular transducers of exercise therapy for reducing OA pain in aging and obese animal models. Our long-term goal is to develop new pharmacologic strategies that are both effective and safe for patients. Our research on this topic is currently supported by a Merit Award from the Veterans Administration.