Early Intervention with cdk9 Inhibitors to Prevent Post-Traumatic Osteoarthritis

Post-traumatic osteoarthritis (PTOA) is a common long-term consequence of joint injuries such as anterior cruciate ligament (ACL) rupture. In this study we used a tibial compression overload mouse model to compare knee injury induced at low speed (1mm/s), which creates an avulsion fracture, to injury induced at high speed (500mm/s), which induces midsubstance tear of the ACL. Mice were sacrificed at 0 days, 10 days, 12 weeks, or 16 weeks post-injury, and joints were analyzed with micro-computed tomography, whole joint histology, and biomechanical laxity testing. Knee injury with both injury modes caused considerable trabecular bone loss by 10 days post-injury, with the Low Speed Injury group (avulsion) exhibiting a greater amount of bone loss than the High Speed Injury group (midsubstance tear). Immediately after injury, both injury modes resulted in greater than twofold increases in total AP joint laxity relative to control knees. By 12 and 16 weeks post-injury, total AP laxity was restored to uninjured control values, possibly due to knee stabilization via osteophyte formation. This model presents an opportunity to explore fundamental questions regarding the role of bone turnover in PTOA, and the findings of this study support a biomechanical mechanism of osteophyte formation following injury. ! 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res XX:XXX–XXX, 2013.