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bioRxiv · 10.1101/2021.09.27.461207

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

Lesage, R.·Ferrao Blanco, M. N.·Narcisi, R.·Welting, T.·van Osch, G. J. V. M.·Geris, L.
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Abstract

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.

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Lesage, R., Ferrao Blanco, M. N., Narcisi, R., Welting, T., van Osch, G. J. V. M., Geris, L.. 2021-09-27. An integrated in silico-in vitro approach for identification of therapeutic drug targets for osteoarthritis. https://doi.org/10.1101/2021.09.27.461207

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