The overall objective of the study is to improve the long-term functional outcomes of Veterans suffering from osteoarthritis (OA) with the use of thymosin 4 (tb4). Tb4 is a protein found to extracellulary inhibit inflammation and promote tissue repair, as demonstrated in multiple animal studies and several investigational studies in humans. The proposal consists of two specific aims, each using a different mouse model of OA to test the hypothesis that tb4 will prevent the development of post-traumatic OA by preventing cartilage degeneration, chondrocyte hypertrophy and apoptosis, subchondral bone sclerosis, and synovial fibrosis. In the first model, surgical destabilization of the knee is used to induce OA. The second model is a non-invasive and utilizes mechanical joint loading. The force utilized does not lead to joint damage when it occurs individually. However, when the force is sustained leads to OA-type changes. These models mimic the post-traumatic OA Veterans develop either after sustaining trauma or after repeated joint stress. In the surgical destabilization of the medial meniscus arm of the study (Specific Aim 1), tb4 will be injected under ultrasound guidance at weekly intervals for 16 weeks, thereby mimicking acute injury and the rehabilitation process. The joint loading arm (Specific Aim 2) mimics the OA that results from recurrent joint stress. Similarly, tb4 will be injected unde ultrasound guidance into the right knee at weekly intervals for 8 weeks. In both arms of the study, control mice will receive PBS. Evaluation of the efficacy of tb4 will be multifaceted with histopathologic scoring, laser scanning confocal microscopy and microbubble ultrasound assessment. Additionally, evaluation of murine functional behaviors will be used to assess the symptomatic consequences of OA and impact of tb4 treatment with dynamic gait analysis and tactile allodynia response. Throughout the study, investigators will be blinded to treatment. Statistical analysis of the data will include the use repeated measures of ANOVA. In keeping with the goals of RR&D CDA-1, Dr. Chauffe will gain essential investigational experience. This will culminate with her ability to successfully work as an independent investigator with a focus on preventing disability due to arthritis. The training plan outlined in this proposal includes extensive educational components, both in the lab and didactic, ensuring this goal is achieved.
Tb4 is a protein that prevents fibrosis and scarring and will be used as the intervention in two mouse models of traumatic osteoarthritis (OA). The VA Health System offers a unique setting for this study, as nearly all Veterans suffer from OA and it is a primary cause of disability in Veterans. The long sought goal in OA has been to discover a disease modifying OA drug but currently no such treatment exists. If successful, the technology can be rapidly applied to studies in humans as the Food and Drug Administration (FDA) has previously accepted of an Investigational New Drug (IND) application for tb4. The goal of this translational study is ultimately aimed at improving the function and independence of Veterans with OA.
