ObjectiveAltered mechanical loading is a known risk factor for osteoarthritis. Destabilization of the medial meniscus (DMM) is a preclinical gold standard model for post-traumatic osteoarthritis and is thought to induce instability and locally increased loading. However, the joint- and tissue-level mechanical environment underlying cartilage degeneration remains poorly documented.DesignUsing a custom multiscale modeling approach, we assessed joint and tissue biomechanics in rats undergoing sham surgery and DMM. High-fidelity experimental gait data were collected in a setup combining biplanar fluoroscopy and a ground reaction force plate. Knee poses and joint-level loading were estimated through musculoskeletal modeling, using bony landmarks, semi-automatically tracked via deep learning on fluoroscopic images, and ground reaction forces. A musculoskeletal model of the rat hindlimb was adapted to represent knee flexion-extension, valgus-varus, and internal-external rotation. The tissue-level cartilage mechanical environment was then spatially estimated, using the musculoskeletal modeling parameters as inputs into a dedicated finite element (FE) model of the rat knee, comprising cartilage and meniscal tissues. Experimental gait data and modeling workflows, including musculoskeletal models and FE meshes, are openly shared through a data repository.ResultsIn rats with DMM, the frontal plane knee pose was altered, yet there was no indication of joint-level overloading. Tissue-level mechanical cues typically linked with cartilage degeneration were not increased in the medial tibial cartilage, despite evidence of tissue structural changes.ConclusionDMM did not increase joint and tissue mechanical responses in the knee medial compartment, suggesting that mechanical loading alone does not explain the observed osteoarthritis-like structural changes.