Mechanical and Biologic Impact of Dynamic Loading on Bovine and Human Models of Osteoarthritis

Both dexamethasone (Dex) and Insulin-like growth factor 1 (IGF-1) have shown promise as disease-modifying therapeutics for osteoarthritis (OA), a disease characterized by cartilage degradation. Additionally, dynamic loading has been demonstrated to affect chondrocyte metabolic activity, with mechanical stimuli acting as a therapeutic at specific amplitudes and frequencies. The goal of this thesis was to investigate the potential of these therapeutics and loading to be synergistic in preventing post-traumatic osteoarthritis (PTOA) disease initiation (e.g., after a traumatic joint injury) and in ameliorating progression of OA. We hypothesized that Dex and IGF-1 could help to maintain the mechanical properties and biochemical composition of cartilage in human osteochondral tissues when treated with exogenous inflammatory cytokines. Bovine knee cartilage and human ankle cartilage-bone explants were used in vitro with a cytokine challenged to mimic an OA disease state. A load-controlled dynamic loading protocol was modeled after a physiologically relevant rehabilitation program and was tested in healthy tissue to optimize the applied stress magnitude and loading duration. The optimized protocol was then used for 7 days duration (at 0.33 Hz, 40% duty cycle for 1 hour per day) +/- Dex and IGF-1 to evaluate biochemical changes on the protein and gene expression levels. Stress-relaxation testing was utilized to calculate mechanical properties of human cartilage, both before and after one 1-hour loading session, at baseline and after treatment with cytokines and Dex. It was found that a load-controlled protocol could mimic exercise with total strain in a physiologically relevant range. Loading after 7 days also increased the effects of Dex and IGF-1 on cell viability, and further increased GAG biosynthesis and decreased GAG loss seen with Dex alone. Notably, in human tissue there was donor-to-donor variability in this response to both loading on its own, and to Dex/IGF-1 with and without loading. While Dex preserved cell viability and decreased GAG loss and NO release from cartilage explants treated with cytokines, Dex did not alter mechanical properties (before or after loading) after 10 days. However, there was variation in these values between donor age groups at baseline. Taken together, these results suggest that a rehabilitative loading therapy in combination with Dex/IGF-1 could enhance certain disease-modifying effects of each of the two drugs, and that inherent tissue variability (between patients) could contribute to individual variation in responses and thus emphasize the need for a personalized medicine approach.S.M