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Transcriptional response of human articular chondrocytes treated with fibronectin fragments: an in vitro model of the osteoarthritis phenotype.
- Source :
-
Osteoarthritis and cartilage [Osteoarthritis Cartilage] 2021 Feb; Vol. 29 (2), pp. 235-247. Date of Electronic Publication: 2020 Nov 25. - Publication Year :
- 2021
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Abstract
- Objective: Fibronectin is a matrix protein that is fragmented during cartilage degradation in osteoarthritis (OA). Treatment of chondrocytes with fibronectin fragments (FN-f) has been used to model OA in vitro, but the system has not been fully characterized. This study sought to define the transcriptional response of chondrocytes to FN-f, and directly compare it to responses traditionally observed in OA.<br />Design: Normal human femoral chondrocytes isolated from tissue donors were treated with either FN-f or PBS (control) for 3, 6, or 18 h. RNA-seq libraries were compared between time-matched FN-f and control samples in order to identify changes in gene expression over time. Differentially expressed genes were compared to a published OA gene set and used for pathway, transcription factor motif, and kinome analysis.<br />Results: FN-f treatment resulted in 3,914 differentially expressed genes over the time course. Genes that are up- or downregulated in OA were significantly up- (P < 0.00001) or downregulated (P < 0.0004) in response to FN-f. Early response genes were involved in proinflammatory pathways, whereas many late response genes were involved in ferroptosis. The promoters of upregulated genes were enriched for NF-κB, AP-1, and IRF motifs. Highly upregulated kinases included CAMK1G, IRAK2, and the uncharacterized kinase DYRK3, while growth factor receptors TGFBR2 and FGFR2 were downregulated.<br />Conclusions: FN-f treatment of normal human articular chondrocytes recapitulated many key aspects of the OA chondrocyte phenotype. This in vitro model is promising for future OA studies, especially considering its compatibility with genomics and genome-editing techniques.<br /> (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- Calcium-Calmodulin-Dependent Protein Kinase Type 1 drug effects
Calcium-Calmodulin-Dependent Protein Kinase Type 1 genetics
Chondrocytes metabolism
Femur
Gene Expression genetics
Humans
In Vitro Techniques
Interferon Regulatory Factors drug effects
Interferon Regulatory Factors genetics
Interleukin-1 Receptor-Associated Kinases drug effects
Interleukin-1 Receptor-Associated Kinases genetics
NF-kappa B drug effects
NF-kappa B genetics
Osteoarthritis metabolism
Peptide Fragments pharmacology
Phenotype
Promoter Regions, Genetic
Protein Serine-Threonine Kinases drug effects
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases drug effects
Protein-Tyrosine Kinases genetics
Receptor, Fibroblast Growth Factor, Type 2 drug effects
Receptor, Fibroblast Growth Factor, Type 2 genetics
Receptor, Transforming Growth Factor-beta Type II drug effects
Receptor, Transforming Growth Factor-beta Type II genetics
Transcription Factor AP-1 drug effects
Transcription Factor AP-1 genetics
Cartilage, Articular cytology
Chondrocytes drug effects
Fibronectins pharmacology
Gene Expression drug effects
Osteoarthritis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9653
- Volume :
- 29
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Osteoarthritis and cartilage
- Publication Type :
- Academic Journal
- Accession number :
- 33248223
- Full Text :
- https://doi.org/10.1016/j.joca.2020.09.006