From Joint Loading to Osteoarthritis: A Multiscale Review of Knee Mechanobiology and Digital Modelling

The knee is a mechanically demanding synovial organ in which joint loading, tissue deformation, cellular mechanotransduction and matrix turnover are coupled. This narrative review critically links those scales and asks where the evidence is sufficiently mature for mechanistic or clinical inference. PubMed/MEDLINE and Europe PMC were searched from database inception to 20 July 2026 using structured terms for knee biomechanics, cartilage and osteochondral mechanobiology, finite element modelling, mechanosensitive channels, osteoarthritis, machine learning and digital twins. Landmark studies were selected for foundational models, while recent studies were prioritised for causal experiments, validation and translation. Instrumented implants show that common activities generate tibiofemoral forces of several times body weight, but tissue-level exposure also depends on muscle co-contraction, geometry and material properties. Biphasic and fibril-reinforced models explain how those loads become stress, strain, fluid pressure and osmotic signals. At the cell scale, TRPV4 and PIEZO1/2 participate in overlapping, context-dependent calcium signalling rather than a universal protective-pathological binary; most causal evidence remains preclinical. Osteoarthritis is therefore framed as a mechanically amplified feedback process involving cartilage, bone, synovium and systemic modifiers. Computational degeneration models and machine-learning surrogates are increasingly informative, although prospective validation, parameter identifiability and uncertainty propagation remain limiting. The review's added value is an explicit transmission-and-validation framework that connects whole-joint observables to molecular responses while labelling the evidence source and translational readiness at every step.