by Atte S. A. Eskelinen, Joonas P. Kosonen, Moustafa Hamada, Amir Esrafilian, Cristina Florea, Alan J. Grodzinsky, Petri Tanska, Rami K. KorhonenDegenerative musculoskeletal diseases like osteoarthritis can be initiated by joint injury. Injurious overloading-induced mechanical straining of articular cartilage and subsequent biological responses may trigger cartilage degradation. One early sign of degradation is loss of aggrecan content which is potentially accelerated near chondral lesions under physiological loading. Yet, the mechanoinflammatory mechanisms explaining time-dependent degradation in regions with disparate mechanical loading are unclear and challenging to assess with experiments alone. Here, we developed computational models unraveling potential mechanisms behind aggrecan content adaptation in fibril-reinforced porohyperelastic cartilage after single injurious overloading (50% compressive strain magnitude, 100%/s strain rate) followed by physiological cyclic loading (15% strain, 1 Hz, haversine waveform). The simulated adaptation of aggrecan content was compared spatially and at several time points to tissue composition found in Safranin-O-stained sections of young bovine knee cartilage subjected to the same loading protocols. Incorporating mechanical strain-driven cell damage and downstream proteolytic enzyme release, fluid flow-driven aggrecan depletion, and fluid pressure-stimulated regulation of aggrecan biosynthesis, the models agreed with experiments and exhibited 14%-points greater near-lesion aggrecan loss after 12 days of physiological loading compared to without loading. The near-lesion aggrecan loss was driven by fluid flow and proteolytic aggrecanase activity, while chondroprotective pro-anabolic responses (increased aggrecan biosynthesis) were prominent in the deeper tissue despite damaged superficial layer. This significant advancement in mechanistic understanding incorporated into cartilage adaptation model can help in development and guidance of personalized therapies, such as rehabilitation protocols and tissue-engineered constructs.