Biology subjects

Lesage, R.

Publications and source records attributed to Lesage, R..

3 recordsLinked to original sources

bioRxiv2025

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

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 Hills function was used to link cellular forces from the FE model to a mechanical loading input to the regulatory network. Hills 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. HighlightsO_LIDeveloped an integrated multiscale model linking tissue, cellular mechanics, and gene regulation in articular cartilage. C_LIO_LICoupled cellular mechanical forces to gene regulatory networks using Hills function approach. C_LIO_LICalibrated Hills function parameters via genetic algorithm using experimental cartilage explant compression data. C_LIO_LIPredicted spatial heterogeneity of chondrocyte activity and cartilage biomarker expression under dynamic compression C_LIO_LIEstablished computational framework can be used for studying cartilage mechanobiology and osteoarthritis therapeutic strategies C_LI

bioengineering↗

bioRxiv2022

Pharmacologic inhibition of EPHA2 decreases inflammation and pathological endochondral ossification in osteoarthritis

Low-grade inflammation and pathological endochondral ossification are processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, data mining on publicly available transcriptomic datasets revealed EPHA2, a receptor tyrosine kinase associated with cancer, to be associated with both inflammation and endochondral ossification in osteoarthritis. A computational model of cellular signaling networks in chondrocytes predicted that in silico activation of EPHA2 in healthy chondrocytes increases inflammatory mediators and triggers hypertrophic differentiation, the phenotypic switch characteristic of endochondral ossification. We then evaluated the effect of inhibition of EPHA2 in cultured human chondrocytes isolated from individuals with osteoarthritis and demonstrated that inhibition of EPHA2 indeed reduced inflammation and hypertrophy. Additionally, systemic subcutaneous administration of the EPHA2 inhibitor ALW-II-41-27 attenuated joint degeneration in a mouse osteoarthritic model, reducing local inflammation and pathological endochondral ossification. Collectively, we demonstrate that pharmacological inhibition of EPHA2 with ALW-II-41-27 is a promising disease-modifying treatment that paves the way for a novel drug discovery pipeline for osteoarthritis.

pharmacology and toxicology↗

bioRxiv2021

An integrated in silico-in vitro approach for identification of therapeutic drug targets for osteoarthritis

Without the availability of disease-modifying drugs, there is an unmet therapeutic need for osteoarthritic patients. During osteoarthritis, the homeostasis of articular chondrocytes is dysregulated and a phenotypical transition called hypertrophy occurs, leading to cartilage degeneration. Targeting this phenotypic transition has emerged as a potential therapeutic strategy. Chondrocyte phenotype maintenance and switch are controlled by an intricate network of intracellular factors, each influenced by a myriad of feedback mechanisms, making it challenging to intuitively predict treatment outcomes. In this study, we developed a regulatory network model using knowledge-based and data-driven modelling technologies. The in silico high-throughput screening of (pairwise) perturbations operated with that network model highlighted conditions impacting the hypertrophic switch. Several combinations were tested in a murine cell line and primary chondrocytes to validate the predicted conditions potential. Our in silico-in vitro strategy opens a new route for developing osteoarthritis targeting therapies by refining the early stages of drug discovery.

systems biology↗