Osteoarthritis (OA), a degenerative disease affecting approximately 27 million Americans, is characterized by cartilage degradation, subchondral bone changes, and joint pain and discomfort. Although OA is hypothesized to occur due to joint instability that stimulates cell-mediated pathologies, the mechanical environment associated with the disease is unknown. In this thesis, a load-induced model of OA was used to elucidate the mechanical environment associated with OA development.

To examine the mechanical nature of joint instabilities in which OA develops in loadinduced and other injury models, we conducted a quasi-static kinematic analysis on cadaver mice. Labeled adult male right joints were subjected to destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT). Left knees remained intact. Roentgen stereophotogrammetric analysis (RSA) was conducted on each joint during loading from 0 to 9N. Intact and DMM joints exhibited consistent and similar kinematics, with the tibia translating proximally and anteriorly, and knee flexion increasing with load. ACLT knees dislocated at 0N, suggesting that OA development in this model may be induced by severe joint instabilities.

Because bone is the primary load-bearing tissue in the joint, we examined the role of subchondral bone properties and remodeling in load-induced OA development. Adult male C57Bl/6 (low bone mass) and FVB (high bone mass) mice were treated with alendronate (ALN) to inhibit bone remodeling or vehicle treatment, and subjected to tibial loading for 1, 2, or 6 weeks. OA was attenuated in FVB mice compared to B6. ALN generally prevented the agerelated cancellous bone mass reduction, but had no effect on load-induced bone changes. ALN treatment attenuated cartilage damage only in FVB mice.

Finally, discrete element analysis was used to characterize the stresses associated with intact joint kinematics from 0-9N. Areas of highest cartilage stresses strongly correlated with locations of most severe tissue damage. To determine the role tissue properties on cartilage stresses, parametric analyses were conducted on a FE contact model. Unlike cartilage properties, modulating bone properties in this model did not significantly affect stresses induced on the cartilage surface. In summary, this thesis characterized the mechanical environment, and changes thereof, associated with load-induced OA pathology.