CSF1-R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury.

Abstract

Knee osteoarthritis contributes substantially to worldwide disability. Post-traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1-R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1-R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four-month-old mice were randomized to receive a CSF1-R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1-R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1-R inhibitor-treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post-injury, CSF1-R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1-R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. KEY POINTS: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1-R. CSF1-R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1-R as a therapeutic target across musculoskeletal tissues after injury.