An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis.
Chondrocyte hypertrophy
Computational modeling
Drug targets
In vitro validation
Network of signal transduction
Osteoarthritis
Regulatory network inference
Virtual cell
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
09 11 2022
09 11 2022
Historique:
received:
28
01
2022
accepted:
27
10
2022
entrez:
10
11
2022
pubmed:
11
11
2022
medline:
15
11
2022
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36352408
doi: 10.1186/s12915-022-01451-8
pii: 10.1186/s12915-022-01451-8
pmc: PMC9648005
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
253Informations de copyright
© 2022. The Author(s).
Références
Database (Oxford). 2017 Jan 1;2017:
pubmed: 28605766
Semin Arthritis Rheum. 2018 Feb;47(4):457-463
pubmed: 28917712
Arthritis Res Ther. 2013 Sep 19;15(5):R126
pubmed: 24286177
Development. 2008 Jun;135(11):1947-56
pubmed: 18434416
Curr Opin Rheumatol. 2019 Jan;31(1):80-89
pubmed: 30461544
Arthritis Rheum. 1992 Jul;35(7):806-11
pubmed: 1622419
Nat Commun. 2018 Jun 22;9(1):2434
pubmed: 29934552
Ann Rheum Dis. 2016 Feb;75(2):449-58
pubmed: 25475114
BMC Syst Biol. 2012 Nov 22;6:145
pubmed: 23173819
Arthritis Res Ther. 2012 Jan 20;14(1):R16
pubmed: 22264237
BMC Med Genomics. 2012 Aug 21;5:35
pubmed: 22909195
Science. 2002 Mar 1;295(5560):1662-4
pubmed: 11872829
Nat Rev Rheumatol. 2017 Nov;13(11):670-681
pubmed: 29021569
J Immunol. 2009 Jun 15;182(12):7937-45
pubmed: 19494318
Sci Rep. 2018 May 29;8(1):8322
pubmed: 29844324
Biostatistics. 2007 Jan;8(1):118-27
pubmed: 16632515
J Biol Chem. 2012 Jan 6;287(2):916-24
pubmed: 22102413
Nat Rev Genet. 2005 Jun;6(6):451-64
pubmed: 15883588
Arthritis Rheum. 2006 Aug;54(8):2462-70
pubmed: 16868966
Ann Rheum Dis. 2016 Mar;75(3):571-7
pubmed: 25550340
Mediators Inflamm. 2020 Mar 3;2020:8293921
pubmed: 32189997
Methods Mol Biol. 2012;804:463-79
pubmed: 22144167
Ann Rheum Dis. 2019 Jan;78(1):100-110
pubmed: 30026257
Arthritis Rheumatol. 2014 Apr;66(4):979-89
pubmed: 24757149
J Cell Biol. 2011 May 2;193(3):551-64
pubmed: 21536751
BMC Bioinformatics. 2006 Mar 20;7 Suppl 1:S7
pubmed: 16723010
Cartilage. 2021 Dec;13(2_suppl):168S-174S
pubmed: 34165367
Nature. 1992 Oct 22;359(6397):693-9
pubmed: 1436033
Nat Med. 2010 Jun;16(6):678-86
pubmed: 20495570
Nat Rev Rheumatol. 2017 Mar;13(3):155-163
pubmed: 28148919
BMC Syst Biol. 2012 Aug 07;6:96
pubmed: 22871178
Arthritis. 2011;2011:683970
pubmed: 22046522
J Orthop Res. 1998 Mar;16(2):207-16
pubmed: 9621895
Am J Pathol. 2003 Jun;162(6):1975-84
pubmed: 12759253
Front Bioeng Biotechnol. 2018 Mar 14;6:22
pubmed: 29594113
Cell Signal. 2020 Apr;68:109471
pubmed: 31837466
Gerontology. 2017;63(1):29-35
pubmed: 27595269
Front Bioeng Biotechnol. 2018 Mar 19;6:18
pubmed: 29616218
Histochem Cell Biol. 2018 Apr;149(4):353-363
pubmed: 29308531
Nat Rev Genet. 2004 Nov;5(11):826-37
pubmed: 15520792
Biochem Biophys Res Commun. 1999 Apr 21;257(3):814-20
pubmed: 10208865
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Dis Model Mech. 2015 Jan;8(1):17-30
pubmed: 25561745
J Tissue Eng Regen Med. 2015 Apr;9(4):332-42
pubmed: 23576364
Nat Genet. 2005 Apr;37(4):382-90
pubmed: 15778709
PLoS One. 2010 Sep 28;5(9):
pubmed: 20927193
Front Genet. 2016 May 31;7:94
pubmed: 27303434
Arthritis Rheum. 2012 Dec;64(12):3982-92
pubmed: 22833219
Bioinformatics. 2006 Jul 15;22(14):e124-31
pubmed: 16873462
Arthritis Rheum. 2012 Jul;64(7):2278-88
pubmed: 22307759
Arthritis Rheum. 2008 Dec;58(12):3788-97
pubmed: 19035497
BMC Syst Biol. 2013 Dec 10;7:135
pubmed: 24321545
Osteoarthritis Cartilage. 2016 Dec;24(12):2013-2021
pubmed: 27492463
PLoS One. 2016 Aug 31;11(8):e0162052
pubmed: 27579819
J Clin Invest. 1996 Feb 1;97(3):761-8
pubmed: 8609233
Endocrinology. 2000 Dec;141(12):4728-35
pubmed: 11108288
Nat Methods. 2012 Jul 15;9(8):796-804
pubmed: 22796662
PLoS Comput Biol. 2019 Jan 24;15(1):e1006685
pubmed: 30677026
Osteoarthritis Cartilage. 2013 Apr;21(4):604-13
pubmed: 23353668
Osteoarthritis Cartilage. 2015 Apr;23(4):616-28
pubmed: 25545425
Cells. 2019 Aug 24;8(9):
pubmed: 31450621
Osteoarthritis Cartilage. 2012 Mar;20(3):223-32
pubmed: 22178514
Development. 2015 Jul 1;142(13):2250-60
pubmed: 26130756
Cytokine. 2000 Jun;12(6):765-9
pubmed: 10843761
Ernst Schering Res Found Workshop. 2007;(61):69-88
pubmed: 17249497
Mol Syst Biol. 2020 Jun;16(6):e9690
pubmed: 33438807
PLoS One. 2015 Jun 11;10(6):e0130033
pubmed: 26067297
Nat Med. 2009 Dec;15(12):1421-5
pubmed: 19915594
BMC Syst Biol. 2012 Oct 18;6:133
pubmed: 23079107
Arthritis Rheum. 2013 Jun;65(6):1547-60
pubmed: 23436205
Arthritis Rheum. 2000 Jan;43(1):195-205
pubmed: 10643716
NPJ Syst Biol Appl. 2019 Nov 11;5:40
pubmed: 31728204
Nat Rev Mol Cell Biol. 2008 Oct;9(10):770-80
pubmed: 18797474
Front Bioeng Biotechnol. 2021 Nov 15;9:732917
pubmed: 34869253
Nat Methods. 2016 Nov 29;13(12):966-967
pubmed: 27898060
Nat Med. 2017 Oct 6;23(10):1113
pubmed: 28985211
Front Bioeng Biotechnol. 2016 Feb 11;4:10
pubmed: 26904540
Arthritis. 2013;2013:461486
pubmed: 23864948
Arthritis Rheum. 2012 Oct;64(10):3256-66
pubmed: 22833266
Mol Cell Biol. 2009 Nov;29(21):5751-62
pubmed: 19704004