Macrophage Senescence Links ACL Injury to Posttraumatic Osteoarthritis and Muscle Atrophy

Traumatic knee injury often leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle atrophy and weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutically targetable mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified Cd163+ anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both quadriceps muscle and knee joint capsule after ligament injury. Furthermore, conditioned media from senescent macrophages induced senescence- and osteoarthritis-related transcriptional programs in mesenchymal progenitors. Clearance of senescent cells using the senolytic cocktail dasatinib + quercetin (D+Q) mitigated ligament injury-induced muscle atrophy and cartilage degradation. Of note, D+Q demonstrated greater senescent cell clearance within muscle compared to cartilage. We also provide clinical evidence of elevated senescent cell burden in quadriceps muscle of patients following ACL injury and with knee PTOA, which is obstinate to standard of care, highlighting cellular senescence as a therapeutic target with strong potential to improve functional recovery after traumatic joint injury.