Connecting Joint Function to Chondrocyte Biology in Knee Osteoarthritis

Objective

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-CONNECT instigates an innovative approach to understanding the fundamental cause of OA by posing a question that could previously never 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 unravel the OA Mechanome, the maladaptive dynamic interplay of mechanical and biological drivers of OA cartilage degeneration across cellular-, tissue- and joint- scales by: (1) Connecting the spatial mechanical and cell molecular dynamics underlying OA cartilage adaptation to loading, using multimodal read-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 mechanobiological processes, 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 the multi-scale model of (2) with machine learning, multi-variate and population-based methods leveraging the use of clinically accessible ‘real-world’ data. Prospective cohort and proof-of-concept studies will capture the dynamics of mechanical and biological 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 required to develop treatment strategies. By dissecting the Goldilocks problem of mechanical load, OA-CONNECT will initiate a groundbreaking shift in unraveling mechanobiological drivers in an uncharted direction.