Project Summary: Post-traumatic osteoarthritis (PTOA) is debilitating due to its early onset, predisposition to affect younger, active individuals and the need for earlier surgical and rehabilitative interventions, all of which decrease quality of life. More broadly, 12% of OA cases are due to joint trauma (12.7 million people), costing $3 billion/yr. Injuries of the anterior cruciate ligament (ACL) and meniscus are the most common concerns that place individuals at increased risk of developing PTOA about the knee. However, a dilemma exists in the treatment of PTOA because we do not understand how the severity of the injury affects the adaptive responses of the limb (muscle, bone, and articular cartilage), nor how these adaptations are modified by concomitant meniscus injury, the subject's sex, BMI and joint geometry. Moreover, it is unknown how these adaptive responses are associated with changes in early markers of the PTOA disease process. These knowledge gaps represent critical barriers to developing more effective, early PTOA treatment paradigms that are informed by an understanding of adaptions in skeletal muscle, bone and articular cartilage. To date, no study has prospectively characterized subjects prior to ACL injury and then evaluated the adaptive response of the limb to ACL rupture and surgical reconstruction. Our current knowledge base is built entirely on retrospective studies, and consequently we propose a prospective study that will evaluate two aims. Aim 1: Characterize the adaptive changes in skeletal muscle size and function, bone architecture, and articular cartilage matrix components that occur in response to severe knee trauma; and determine how these changes differ depending on the type of trauma (ACL disruption with and without concomitant injury to the menisci), the patient's sex, BMI, and joint geometry. Aim 2: Assess the effects of severe knee trauma on change in thickness of the articular cartilage (an early marker of PTOA) and determine if these effects are modified by structures involved in the trauma (ACL disruption with and without concomitant meniscus injury), the patient's sex, BMI, and joint geometry; and mediated by adaptive changes in skeletal muscle size and function, bone architecture, and articular cartilage matrix components. The study will provide data on the integrative, adaptive response of multiple tissues of the injured limb to knee trauma and surgery and builds logically upon the parent investigation. The study will provide a mechanistic understanding of the evolution of knee joint pathology that leads to PTOA, and the modifying effects of sex, BMI and joint geometry. Knowledge from this study will address critical barriers to progress in PTOA treatment by determining how the severity of the trauma affects cartilage structure at a time when interventions will be effective for prevention of incident or worsening PTOA: the barrier to trials focused on treatment of PTOA.