Acute loading injuries and their relation to post-traumatic osteoarthritis in a preclinical model

Purpose: Up to 50% of knee injuries that result in tears of the ACL progress to post-traumatic OA (ptOA) within 10-15 years of the initial trauma. This represents an almost 5-fold increase in risk compared to non-injured joints, with current interventions (including surgical reconstruction) not significantly altering OA risk. Factors other than altered biomechanics may therefore play a significant role in disease development. Risk, rate of onset, and progression of ptOAmay be linked to the traumau0027s impact severity and the joint structures affected both acutely and chronically. A better understanding of the interaction of these variables may improve prognostic capability and enable the development of specific treatments for injury management and disease prevention. In the present study we investigated the relationships between age, gender, body mass, joint load, ACL rupture, and ptOA pathology using a murine model of non-surgical ACL rupture. Methods: ACL injury was induced by a single, axial compressive load to the flexed knee of themouse. At the peak load,10-15 seconds of sustained compression was applied before release. An initial cadaveric study assessed ACL failure loads over a range of mouse biometrics (9-52 week old, male and female C57BL-6, n1⁄4164). The failure load was determined from force-displacement curves and the mode of failure by microscopic evaluation. The potential predictors of these outcomes were assessed using mixed model linear regression and mixed model multinomial logistic regression. A subsequent in vivo study loaded the knees of anaesthetisedmice (10-12 week, male C57Bl-6) to either failure or 55% of the mean failure. Joint pathology was assessed histologically at 2 or 4 weeks post-injury (n1⁄47) in both the medial and lateral compartments. Results: In the cadaveric study, damage induced by loading was largely restricted to the ACL with little evidence of injury to other joint tissues. The ACL was consistently ruptured but the mode of failure varied between specimens. Ruptures occurred towards the femoral insertion with 16% of tears entirely midsubstance, 35% total avulsion fractures and 49% demonstrating a mixture of the two. Logistic regression determined that there was no effect of age, mass, rupture load or joint stiffness on the mode of failure. However, when comparing males and females with avulsion fractures, the relative risk for females was 7.11 (95% CI [1.36 37.07]). The ACL rupture load itself was demonstrated to have a positive association with mass (p u003c 0.001) but not age or gender when correcting for other covariates. In the in vivo study, complete ACL rupture resulted in significant femorotibial OApathology, particularly towards theposterior region and greatest in the medial compartment. At 2 weeks substantial synovitis, tibio-femoral cartilage erosion and structural damage to themedialmeniscuswere evident. By 4 weeks cartilage erosion progressed and subchondral bone sclerosis, osteophytes and enthesophytes developed. In contrast, subfailure loading of the knee resulted in only mild OA pathology. In these knees the ACL remained intact and there was no evidence of synovitis or osteophyte development. There was mild cartilage damage (unlike ACL failure this was similar in medial and lateral compartments) with significant progression from2 to 4weeks. Avery localised subchondral bone remodelling response was also evident posteriorly in the tibia. Conclusions: In this model ACL failure loads have been established for a range of mouse biometrics and were shown to be independent of the age and sex of the mouse. In vivo, complete ACL failure results in the rapid onset of pathology with a clinically relevant pattern of OA change in all other joint tissues. At the early time points examined in this study, mechanical loading alone (no ACL rupture) induces mild changes largely restricted to the cartilage, although this may progress further given more time. Comparisons with other loading regimes and surgical models of ptOA may further illuminate the complex interactions that occur between different joint tissues and risk factors for ptOA.