[en] 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 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. It was implemented using a semi-quantitative formalism, capturing the directional and qualitative interplay between mechanical and inflammatory stimuli on chondrocyte biology, rather than quantitatively predicting absolute gene expression levels. A Hill's function was applied to link cellular forces from the FE model to a mechanical loading input to the regulatory network. Hill's function constants were calibrated through a genetic algorithm by matching simulated and experimental gene expressions of COL-II and ADAMTS5 in cartilage explants under 20% cyclic compression. As a validation step, model simulations were performed at 10% cyclic compression of cartilage explants. Predicted sGAG loss matched the trend of experimental data. COL-II and ACAN were overestimated and ADAMTS5 was underestimated compared with experimental data. These discrepancies are consistent with the semi-quantitative nature of the model and are attributed to the simplified representation of inflammation-dominated catabolic pathways at low mechanical loads in the current framework. Simulated chondrocyte responses at different locations revealed spatial heterogeneity in chondrocyte activity. Overall, the multiscale modeling workflow developed in this study represents a first step towards a powerful platform for mechanistically deciphering the complex interplay of mechanics and inflammation in articular cartilage across multiple length scales.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Mukherjee, Satanik ; Biomechanics Section, KU Leuven, Leuven, Belgium, Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium. Electronic address: satanik.mukherjee@kuleuven.be
Lesage, Raphaelle; Biomechanics Section, KU Leuven, Leuven, Belgium, Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
Geris, Liesbet ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique
Language :
English
Title :
A multiscale modeling approach to study the role of mechanics and inflammation in the pathophysiology of articular cartilage.
Belgian Federal Government ERC - European Research Council European Union. Marie Skłodowska-Curie Actions
Funding text :
This study received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No. 721432 (CarBon project), the In Silico World project (grant agreement No. 101016503), the European Research Council Consolidator Grant No. 101088919 and the Belgian Federal Public Service Policy & Support (grant DigiTwin4PH). The funding sources had no role in the design and execution of the study.
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