論文 - 詳細
| RRC ID | 74836 |
|---|---|
| 著者 | Lesage R, Ferrao Blanco MN, Narcisi R, Welting T, van Osch GJVM, Geris L. |
| タイトル | An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis. |
| ジャーナル | BMC Biol |
| Abstract |
BACKGROUND: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, while in silico modeling can help unravel that complexity. In this study, we aim to develop a virtual articular chondrocyte to guide experiments in order to rationalize the identification of potential drug targets via screening of combination therapies through computational modeling and simulations. RESULTS:We developed a signal transduction network model using knowledge-based and data-driven (machine learning) modeling technologies. The in silico high-throughput screening of (pairwise) perturbations operated with that network model highlighted conditions potentially affecting the hypertrophic switch. A selection of promising combinations was further tested in a murine cell line and primary human chondrocytes, which notably highlighted a previously unreported synergistic effect between the protein kinase A and the fibroblast growth factor receptor 1. CONCLUSIONS:Here, we provide a virtual articular chondrocyte in the form of a signal transduction interactive knowledge base and of an executable computational model. Our in silico-in vitro strategy opens new routes for developing osteoarthritis targeting therapies by refining the early stages of drug target discovery. |
| 巻・号 | 20(1) |
| ページ | 253 |
| 公開日 | 2022-11-9 |
| DOI | 10.1186/s12915-022-01451-8 |
| PII | 10.1186/s12915-022-01451-8 |
| PMID | 36352408 |
| PMC | PMC9648005 |
| MeSH | Animals Cartilage, Articular* / metabolism Chondrocytes / metabolism Humans Hypertrophy / metabolism Mice Osteoarthritis* / drug therapy Osteoarthritis* / genetics Osteoarthritis* / metabolism Signal Transduction |
| IF | 6.765 |
| リソース情報 | |
| ヒト・動物細胞 | ATDC5(RCB0565) |