OA-CONNECT · Connecting Joint Function to Chondrocyte Biology in Knee Osteoarthritis

Osteoarthritis (OA), a degenerative joint disease, debilitates the lives of 242 million people globally but remains without a cure.The knee joint is most frequently affected, causing pain, loss of joint function, and reduced quality of life. OA-CONNECTinstigates an innovative approach to understanding the fundamental cause of OA by posing a question that could previouslynever be answered: ‘What causes mechanical loads to switch from supporting to disrupting cartilage health in OA?’OA-CONNECT introduces a unique, integrated approach CONNECT-ing joint function to chondrocyte biology to unravelthe OA Mechanome, the maladaptive dynamic interplay of mechanical and biological drivers of OA cartilage degenerationacross cellular-, tissue- and joint- scales by:(1) Connecting the spatial mechanical and cell molecular dynamics underlying OA cartilage adaptation to loading, using multimodalread-outs from spatial omics, functional microscopy, and high-field MRI.(2) Predicting cartilage degeneration by connecting knee joint cartilage loads during movement to local cellular mechanobiologicalprocesses, using a multi-scale mechanobiology-inspired adaptive modeling framework informed by datasets of (1).(3) Elucidating cartilage degeneration probability and mechanotherapy success in subjects with early knee OA, integrating themulti-scale model of (2) with machine learning, multi-variate and population-based methods leveraging the use of clinicallyaccessible ‘real-world’ data. Prospective cohort and proof-of-concept studies will capture the dynamics of mechanical andbiological drivers and the impact of three current mechanotherapies.The field of OA needs a shift in focus as the approaches of the past 20 years could not bring the mechanistic insights requiredto develop treatment strategies. By dissecting the Goldilocks problem of mechanical load, OA-CONNECT will initiate agroundbreaking shift in unraveling mechanobiological drivers in an uncharted direction.