A multiscale modeling approach to study the role of mechanics and inflammation in pathophysiology of articular cartilage

Abstract Mechanical loading regulates chondrocyte health in articular cartilage. While physiological stimuli maintain homeostasis, supra-physiological stimuli from joint injuries disrupt it, leading to osteoarthritis (OA). OA is a prevalent degenerative joint disease affecting millions worldwide. OA progression involves complex mechanical and biochemical interactions across multiple length scales, which are challenging to investigate experimentally. In silico models provide an effective framework to explore these mechanisms. This study developed an integrated multiscale modeling framework for articular cartilage. It combined finite element (FE) models at tissue and cellular scales with an intracellular gene/protein regulatory network. The network incorporated key chondrocyte mechanotransduction and inflammatory pathways. A Hill’s function was used to link cellular forces from the FE model to a mechanical loading input to the regulatory network. Hill’s function constants were calibrated using a genetic algorithm approach. Calibration was performed by matching experimental and simulated expressions of COL-II and ADAMTS5 of cartilage explants under 20% dynamic compression. As a validation step, model simulations were performed at 10% dynamic compression of cartilage explants. COL-II and ACAN were overestimated, and ADAMTS5 was underestimated compared with experimental data. Furthermore, predicted sGAG loss matched the trend of experimental data. Simulated chondrocyte responses for varying spatial locations revealed spatial heterogeneity of chondrocyte activity. Over-all, the multiscale modeling workflow developed in this study provides a first step towards a powerful tool to increase the understanding of the complex interplay of mechanics and inflammation in articular cartilage. By integrating tissue, cellular, and intracellular scales, it offers a comprehensive framework for studying cartilage mechanobiology and guiding future therapeutic strategies. Highlights Developed an integrated multiscale model linking tissue, cellular mechanics, and gene regulation in articular cartilage. Coupled cellular mechanical forces to gene regulatory networks using Hill’s function approach. Calibrated Hill’s function parameters via genetic algorithm using experimental cartilage explant compression data. Predicted spatial heterogeneity of chondrocyte activity and cartilage biomarker expression under dynamic compression Established computational framework can be used for studying cartilage mechanobiology and osteoarthritis therapeutic strategies