For more than 40 years, I have conducted basic, translational, and clinical research directed toward advancing understanding the musculoskeletal tissues, injuries and diseases of these tissues and methods of restoring musculoskeletal function following injury or disease. During my first two years in medical school, as I studied cell and molecular biology and pathology, I found the relationships and interactions between cells and their extracellular matrices (ECM), and the relatively unknown organization and structure of the ECM, fascinating. To pursue these interests I took leave from medical school to conduct research and earn a MS degree in Pathology. As much as anything, my interest in connective tissue biology and pathophysiology, led me to choose Orthopaedic Surgery as a specialty and investigate the ultrastructure and aging of the human intervertebral disc. I was fortunate that this work attracted the attention of Dr. Larry Rosenberg at NYU. He invited me to work with him on studies of connective tissue proteoglycans:I eagerly accepted his offer. To further develop this line of research I sought an NIH Research Training Grant Fellowship and took leave from residency. As I gained experience in Orthopedics it became clear to me that osteoarthritis (OA) was a common disabling disease that remained poorly understood – a lack of knowledge that has prevented discovering of methods of preventing or slowing the progression of the disease. This stimulated me to direct my efforts towards cartilage biology and the pathophysiology of OA. Dr. Henry Mankin at Harvard and Dr. Ignacio Ponseti at Iowa encouraged and help guide my studies. Recognizing that the two universal risk factors for OA are aging and joint mechanical overload or injury, along with my collaborators, I studied these factors; and, some results suggest that the two factors interact, that is at least some of the aging changes in chondrocyte function mimic changes caused by mechanical overloading. An idea supported by the clinical evidence that increasing age increases the risk and shortens time of onset of PTOA after joint injuries. Over the last 15 years I have focused most of my research on discovering how mechanical overloading of synovial joints causes OA and how to prevent articular cartilage degradation due to excessive joint loading and injury. Recent major projects include studies of how joint overloading causes OA in humans and animals, and interventions that interrupt deleterious biologic responses to joint overloading. Through these studies, our research team of clinicians, biologists and bioengineers has identified cellular responses to joint overloading that cause progressive cartilage erosion and promising methods of preventing cartilage loss. Our most recent work shows that mechanically induced chondrocyte metabolic dysfunction has a critical role in the onset and progression of OA and that preventing this chondrocyte dysfunction in animal models minimizes or prevents cartilage erosion following joint injury. We have identified the barriers to applying this knowledge to clinical practice and designed the current proposal, Translating Metabolic Responses to Mechanical Insult into Early Interventions to Prevent PTOA, to overcome these barriers. .