期刊
OSTEOARTHRITIS AND CARTILAGE
卷 29, 期 2, 页码 235-247出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2020.09.006
关键词
Osteoarthritis; Chondrocytes; Cartilage; Fibronectin; RNA-seq
资金
- National Institute of Arthritis, Musculoskeletal, and Skin Disease [R37-AR049003]
- National Institute on Aging [RO1-AG044034]
- National Human Genome Research Institute [R00-HG008662]
- National Institute of General Medical Sciences [R35-GM128645, T32GM007092]
- Klaus Kuettner Chair for Osteoarthritis Research
Treatment of normal human articular chondrocytes with fibronectin fragments can recapitulate key aspects of the osteoarthritis chondrocyte phenotype, showing promising potential for future osteoarthritis studies, especially considering its compatibility with genomics and genome-editing techniques.
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. 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. Results: FN-f treatment resulted in 3,914 differentially expressed genes over the time course. Genes that are upor 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 -KB, 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. 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. (c) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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