Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis
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 mechanotransductio...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1006066/full |
| _version_ | 1811173170487492608 |
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| author | Maria Segarra-Queralt Gemma Piella Jérôme Noailly |
| author_facet | Maria Segarra-Queralt Gemma Piella Jérôme Noailly |
| author_sort | Maria Segarra-Queralt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T17:42:20Z |
| format | Article |
| id | doaj.art-94f6e7657aff4842a2eb4e9788a1c4a3 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-04-10T17:42:20Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-94f6e7657aff4842a2eb4e9788a1c4a32023-02-03T10:54:55ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852023-02-011110.3389/fbioe.2023.10060661006066Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritisMaria Segarra-QueraltGemma PiellaJérôme NoaillyOsteoarthritis (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.https://www.frontiersin.org/articles/10.3389/fbioe.2023.1006066/fullmechanobiologymechanotransductionchondrocytenetwork-based modelosteoarthritissystems biology |
| spellingShingle | Maria Segarra-Queralt Gemma Piella Jérôme Noailly Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis Frontiers in Bioengineering and Biotechnology mechanobiology mechanotransduction chondrocyte network-based model osteoarthritis systems biology |
| title | Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis |
| title_full | Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis |
| title_fullStr | Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis |
| title_full_unstemmed | Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis |
| title_short | Network-based modelling of mechano-inflammatory chondrocyte regulation in early osteoarthritis |
| title_sort | network based modelling of mechano inflammatory chondrocyte regulation in early osteoarthritis |
| topic | mechanobiology mechanotransduction chondrocyte network-based model osteoarthritis systems biology |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2023.1006066/full |
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