Intervention Window for Knee Posttraumatic Osteoarthritis Appears as Early as 1 Week Post Anterior Cruciate Ligament Injury With Macrophage and Osteoclast as Potential Therapeutic Targets in a Rat Model

PURPOSE: To explore the timing of initiating early intervention and potential therapeutic targets for posttraumatic osteoarthritis (PTOA) by characterizing the pathologic trajectory changes in an anterior cruciate ligament transection (ACLT)-induced rat PTOA model. METHODS: Forty-eight healthy male Sprague-Dawley rats were used to establish the PTOA rat model. Rat knee specimens were collected consecutively at days 1, 3, 7, 10, 14, 21, 28, and 35 after ACLT (n = 6). The macroscopic morphology was evaluated by hematoxylin and eosin staining and three dimensional reconstructed micro-computed tomography images. Synovial inflammation was evaluated by F4/80 immunohistochemistry, myeloperoxidase staining, and immunofluorescent staining of CD206 and iNOS. Cartilage degradation was evaluated by immunohistochemistry staining with safranin O/fast green and MMP13. Subchondral bone remodeling was evaluated by micro-computed tomography and semiquantitative analysis of the ratio of bone volume over tissue volume, trabecular separation, and subchondral bone plate thickness. The cellular dynamics involved in subchondral remodeling were evaluated by staining with tartrate-resistant acid phosphatase, cathepsin K, and Osterix and receptor activator of nuclear factor kappa-B ligand. The specimens were then evaluated by 3 blinded observers using the Osteoarthritis Research Society International scoring systems. RESULTS: Rat knee joint exhibited detectable changes in macroscopic appearance from day 7 after ACLT. Neutrophils infiltrated the synovium rapidly, peaking at day 1 after ACLT and significantly decreasing from day 3. Macrophage infiltration displayed 2 distinct waves at days 7 (principally M1) and 14 (principally M2). The osteoclast activity significantly increased from day 3 after ACLT. From days 7 to 35, increasing cartilage degradation occurred with simultaneous subchondral bone remodeling. CONCLUSIONS: Intervention window for PTOA appears as early as 1 week with macrophage in the synovium and osteoclast in the subchondral bone as potential therapeutic targets. CLINICAL RELEVANCE: Earlier advancement of the intervention time window (1 week) for clinical PTOA may be required, taking macrophages and osteoclasts as potential therapeutic targets, while the specific timepoints need further elucidation.