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Title: Use of a Glucocorticoid to Mitigate Post-Traumatic Osteoarthritis Development in the Ovine Knee
Author: Barton, Kristen
Advisor: Hart, David
Shrive, Nigel
Keywords: Medicine and Surgery
Abstract: After knee ligament injury, specifically anterior cruciate ligament (ACL) injury, the articular surface frequently becomes damaged and can lead to post-traumatic osteoarthritis (PTOA). PTOA is a common joint disease and involves the breakdown of the cartilage that covers the ends of the articular joint-bone interface. PTOA development can be attributed to many factors, two of which may be altered kinematics and joint inflammation. Presently, no treatment options are effective in slowing PTOA progression. Therefore, it is crucial to better understand both joint biomechanics and inflammation. Further, studying interventions that have the potential to mitigate inflammation is necessary to find strategies that may prevent the damage from setting in. Therefore, the rationale for this thesis was to 1) determine if partial ACL (p-ACL) transection (Tx) model leads to PTOA (Project A), 2) determine if p-ACL Tx leads to kinematic alterations (Project B), and 3) determine if p-ACL Tx induced joint inflammation can be modified by glucocorticoid (GC) treatment (Project C). We hypothesized that early inflammation following p-ACL Tx in an ovine model would initiate degeneration of the knee joint and that methylprednisolone acetate (MPA; Depo-Medrol®) treatment would mitigate injury-related PTOA development. Furthermore, MPA would provide a mechanism of long-term prevention to joint damage by suppressing acute inflammation. The results showed that p-ACL Tx led to significantly more combined gross damage at 40 weeks post p-ACL Tx than the control group. There was considerable inter-subject variability following p-ACL knee injury within animals. There were consistent changes in medial-lateral, posterior-anterior, and inferior-superior translations at 40 weeks from intact to after p-ACL Tx. In normal explants, MPA treatment suppressed IL-1β induced mRNA levels for matrix metalloproteinases (MMPs) in articular cartilage, synovium, and infrapatellar fat pad (IPFP) and was found to be tissue-, location-, and gene-specific. Although the gross damage was not significant at 20 weeks post p-ACL Tx compared to the control group, there were trends indicating that the damage was progressive over time and that MPA mitigated gross damage at 20 weeks post p-ACL Tx. The in vivo 20 week studies provided efficacy to determine if we could detect changes early. However, perhaps a greater differential in PTOA damage is necessary to see an impact of GC treatment in a long- term model, comparable to that observed in the 40 weeks post p-ACL Tx group. Last, there were no significant bone changes at either the early 20 weeks post p-ACL Tx or the advanced 40 weeks post p-ACL Tx, compared to non-operative control tibias in any of the subchondral bone layers, thus suggesting the degree of joint instability (full ACL Tx vs. p-ACL Tx) appears to influence the response in bone microarchitecture.
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