Anterior cruciate ligament (ACL) injury is one of the most devastating injuries that commonly occurs during jumping and cutting sports such as basketball, soccer, skiing, and football. Post-traumatic osteoarthritis (PTOA) is a pervasive health issue that is initiated by joint injuries such as ACL injury, articular cartilage or meniscus injury, or intra-articular fracture. The proportion of symptomatic OA patients that can be classified as PTOA is at least 12%, and this etiology typically affects a much younger population than idiopathic (primary) OA. PTOA typically becomes symptomatic within 10-20 years after injury and can significantly affect a patient’s quality of life. In human patients, ACL injuries are often treated with surgical ACL reconstruction, which replaces the injured ligament and partially restores the mechanical stability of the joint. However, it is currently unclear how effective ACL reconstruction is at preventing the progression of PTOA, and what mechanisms may still be present during the entire therapeutic process that can contribute to joint degeneration. The overall goal of this research is to use preclinical models to determine how biomechanical interventions such as surgery (joint restabilization), unloading (rest or disuse), and mechanical loading (exercise) can be utilized following ACL injury to affect the initiation and progression of PTOA.

In our first study, we used non-invasive ACL rupture in mice followed by restabilization surgery to assess the effects of joint instability on PTOA progression. In our second study, we used the same ACL injury and restabilization models, but injury and surgery were separated by one week of either normal cage activity or hindlimb unloading (HLU) to create a non-weightbearing environment during the early phase after injury to allow us to investigate the effect of early unloading. In our third study, mice were injured and unloaded for one week following injury, then started an exercise program with either low intensity (6 m/min) or moderate intensity (12 m/min) exercise for 30 minutes, 5 days/week. We looked at the subchondral bone and osteophyte formation using microCT, we assessed synovitis and articular cartilage degeneration using histology. We also used RT-PCR and in vivo fluorescence imaging to evaluate inflammatory response. We further analyzed immune cell changes following injury and HLU with single-cell RNA sequencing. Gait and functional analyses were performed to investigate pain behaviors. Muscle mass and composition changes were also evaluated to assess the effect of exercise.

In our first study, we found that surgically restabilizing the knee joint with an extracapsular suture immediately after ACL injury in mice slowed PTOA progression and diminished osteophyte formation. In our second study, we found that joint unloading between ACL rupture and surgical restabilization can also slow or prevent PTOA progression based on μCT and histological results. Additionally, our single cell RNA sequencing revealed that one week of HLU resulted in greater number of neutrophils and fewer macrophages and B cells in the injured joint which might suggest some delay in inflammatory responses. In our third study, we showed that one week of low intensity exercise was able to mitigate epiphyseal trabecular bone loss caused by the ACL rupture (-18% BV/TV compared to -28% in mice without exercise), and less osteophyte formation was observed in mice that completed low-intensity exercise compared to the other groups at week 6. Altogether, these results suggest that unloading the joint during the acute phase following ACL injury is critical and low-intensity exercise after restabilizing joints is also beneficial. This study will help inform rehabilitation strategies or recommended activities for human subjects after ACL reconstruction.