Investigation of Post-Traumatic Osteoarthritis using a Novel Knee Injury Model in Mice

Post-traumatic osteoarthritis (PTOA) is commonly a long-term consequence of traumatic joint injury, with approximately 50% of individuals with anterior cruciate ligament (ACL) rupture or meniscectomy developing PTOA within 10-20 years. Mechanisms of PTOA development include changes in the biomechanical stability and mechanical loading of the joint, injury-induced inflammation, and increased rates of subchondral bone and articular cartilage remodeling. However, the relative contributions of these mechanisms to PTOA development are not fully known. Surgical repair of ligaments in humans can effectively restore the biomechanical stability an injured joint, however, these patients are still at an increased risk for developing PTOA, suggesting a mechanism that is not driven exclusively by biomechanical changes.

The long-term goal of this research is to determine the time course and mechanisms of PTOA progression and investigate therapies that can be applied at the time of injury that will slow or prevent the onset of PTOA. In our lab we have developed a novel non-invasive mouse knee injury model that uses a single cycle of tibial compression overload to rupture the ACL, inducing inflammation and biomechanical changes in the joint. This injury method is a significant step forward for mouse models of PTOA since it creates a joint injury response relevant to traumatic joint injury in humans. Other mouse models of PTOA initiate symptoms using various non-physiologic methods such as injection of collagenase, surgical transection of ligaments, or multiple bouts of mechanical loading, all of which fail to mimic clinically relevant injury conditions. Studies using our injury model have shown an increase in joint laxity after injury, significant and immediate inflammation, rapid and considerable remodeling of subchondral bone, and degeneration of articular cartilage.

This mouse model was developed in my laboratory in collaboration with Dr. Dominik R. Haudenschild in the Department of Orthopaedics. We have spent the last several years characterizing this new model and establishing the time course of bone and cartilage changes that occur following knee injury in mice. Our current work will further characterize the biomechanical factors contributing to musculoskeletal changes, quantify inflammation and early biological response following injury, and begin to investigate potential therapies aimed at preventing or slowing the onset of PTOA.