Comparison of innate and adaptive immune responses to joint injury during the onset and progression of post-traumatic osteoarthritis in common murine models

Post-traumatic osteoarthritis (ptOA) following joint injury accounts for at least 12% of cases of symptomatic OA. Surgical restoration of joint biomechanics does not prevent ptOA development, suggesting other factors influence individual OA risk. One suggested factor is the immuno-inflammatory response in the joint, with both adaptive and innate immune responses implicated. Whether different joint injuries incite different acute inflammatory responses, potentially explaining variable ptOA risk, has not been explored. Male 10-12-week-old C57BL/6 mice were randomly assigned to one of 6 interventions: naïve non-operated-controls (NOC), sham surgery (SHAM), anterior cruciate ligament (ACL) sprain (ACLS - subcritical loading injury without ACL damage or ptOA development), ACLR (non-surgical ACL rupture), ACLT (surgical ACL transection), and surgical destabilization of the medial meniscus (DMM). Tissues were harvested at 8 time points spanning acute injury (day-1, -2, -7), and early (day-14), progressive (day-28, -42), and established/advanced (day-56, -70) ptOA development. Immune cells from the synovium and primary and secondary lymphatic organs were analysed using dedicated flow cytometry panels, and joints were evaluated using an established histopathological scoring system. Joint injuries that induced ptOA had a distinct spatiotemporal Th1 and Th 17 response in synovial tissue and draining lymph node with little systemic change. The Th1 response subsided once the cartilage damage reached its maximum, whereas Th17 cells continuously accumulated in the synovial tissue. Importantly, model-specific temporal differences in both Th1/Th2 and Th17/Treg cells were observed. Joint injury also led to a distinct pattern of monocyte cell numbers across tissues. In particular, a short-term (up to day-14) depletion of classically-activated Ly6Chigh monocytes in bone marrow and spleen was concordant with a synovial tissue influx indicating recruitment of systemic cells in ptOA-inducing injuries. This data indicates a predominant loco-regional and limited systemic response to joint injury. The magnitude and duration of the initial transient increase in activated-monocyte and M1 macrophages, and both acute and long-term Th1 and Th17 T-cell response, differentiated pt-OA-inducing from non-ptOA-inducing injury. Importantly, what you injure (ACL vs. meniscus) rather than how you injure it (surgery vs. non-surgical) determines the temporal pattern and systemic involvement of both the innate and adaptive immune response and the structural ptOA progression and severity.