Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis

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• dc.contributor.author Segarra-Queralt, Maria
• dc.contributor.author Piella Fenoy, Gemma
• dc.contributor.author Noailly, Jérôme
• dc.date.accessioned 2023-03-15T14:15:48Z
• dc.date.available 2023-03-15T14:15:48Z
• dc.date.issued 2023
• dc.description.abstract Osteoarthritis (OA) is a debilitating joint disease characterized by articular cartilage degradation, inflammation and pain. An extensive range of in vivo and in vitro studies evidences that mechanical loads induce changes in chondrocyte gene expression, through a process known as mechanotransduction. It involves cascades of complex molecular interactions that convert physical signals into cellular response(s) that favor either chondroprotection or cartilage destruction. Systematic representations of those interactions can positively inform early strategies for OA management, and dynamic modelling allows semi-quantitative representations of the steady states of complex biological system according to imposed initial conditions. Yet, mechanotransduction is rarely integrated. Hence, a novel mechano-sensitive network-based model is proposed, in the form of a continuous dynamical system: an interactome of a set of 118 nodes, i.e., mechano-sensitive cellular receptors, second messengers, transcription factors and proteins, related among each other through a specific topology of 358 directed edges is developed. Results show that under physio-osmotic initial conditions, an anabolic state is reached, whereas initial perturbations caused by pro-inflammatory and injurious mechanical loads leads to a catabolic profile of node expression. More specifically, healthy chondrocyte markers (Sox9 and CITED2) are fully expressed under physio-osmotic conditions, and reduced under inflammation, or injurious loadings. In contrast, NF-κB and Runx2, characteristic of an osteoarthritic chondrocyte, become activated under inflammation or excessive loading regimes. A literature-based evaluation shows that the model can replicate 94% of the experiments tested. Sensitivity analysis based on a factorial design of a treatment shows that inflammation has the strongest influence on chondrocyte metabolism, along with a significant deleterious effect of static compressive loads. At the same time, anti-inflammatory therapies appear as the most promising ones, though the restoration of structural protein production seems to remain a major challenge even in beneficial mechanical environments. The newly developed mechano-sensitive network model for chondrocyte activity reveals a unique potential to reflect load-induced chondroprotection or articular cartilage degradation in different mechano-chemical-environments.
• dc.description.sponsorship The Funding was provided by the Generalitat de Catalunya (Grant No. 2020 FI B 00680); the European Commission (Grant No. MSCA-2020-ITN-ETN GA: 955735) and the European Research Council (ERC-2021-CoG-O-Health-101044828); and the Spanish Ministry of Science and Innovation and Spanish Research State Agency (Grant No. STRATO-PID2021-126469OB-C21).
• dc.format.mimetype application/pdf
• dc.identifier.citation Segarra-Queralt M, Piella G, Noailly J. Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis. Front Bioeng Biotechnol. 2023;11:1006066. DOI: 10.3389/fbioe.2023.1006066
• dc.identifier.doi http://dx.doi.org/10.3389/fbioe.2023.1006066
• dc.identifier.issn 2296-4185
• dc.identifier.uri http://hdl.handle.net/10230/56244
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Frontiers in Bioengineering and Biotechnology. 2023;11:1006066.
• dc.relation.isreferencedby https://www.frontiersin.org/articles/10.3389/fbioe.2023.1006066/full#supplementary-material
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/955735
• dc.relation.projectID info:eu-repo/grantAgreement/EC/HORIZON/101044828
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-126469OB-C21
• dc.rights © 2023 Segarra-Queralt, Piella and Noailly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword mechanobiology
• dc.subject.keyword mechanotransduction
• dc.subject.keyword chondrocyte
• dc.subject.keyword network-based model
• dc.subject.keyword osteoarthritis
• dc.subject.keyword systems biology
• dc.title Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion