Mechanobiology of osteoarthritis: from mechanical-dose sensing to organelle homeostasis and the emerging concept of mechanical memory

Osteoarthritis (OA) is a heterogeneous whole-joint disease in which mechanical, inflammatory, metabolic, and age-related factors converge to disrupt tissue homeostasis. Mechanical loading is essential for cartilage maintenance, whereas excessive or insufficient mechanical stimulation may disrupt cartilage homeostasis depending on the loading modality, magnitude, frequency, duration, recovery conditions, and tissue context. In this review, we integrate OA mechanobiology across scales, from whole-joint load redistribution and tissue-level mechanical filtering to chondrocyte mechanosensing and intracellular responses. The mechanistic emphasis is on cartilage and chondrocytes within the broader whole-joint context of OA. We discuss how integrin-focal adhesion complexes, PIEZO1/2, TRPV4, primary cilia, the cytoskeleton, and nuclear mechanotransduction regulate matrix metabolism, mitochondrial redox homeostasis, autophagy and mitophagy, regulated cell death, and cellular senescence. We further highlight mechanical unloading, immobilization, and microgravity-related models as distinct experimental contexts and discuss epigenetic, epitranscriptomic, and ubiquitin-dependent regulation as potential mechanisms underlying persistent cellular reprogramming, while recognizing that mechanical memory after stimulus withdrawal remains insufficiently established in OA. Finally, we outline how subject-specific modeling, spatial multi-omics, joint-on-chip systems, and multimodal mechanical phenotyping may support mechanobiology-guided OA stratification and therapy. Restoring patient-specific mechanical homeostasis, rather than simply reducing loading, may provide a framework for precision management of OA.