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Abstract Number: 1564

The Comprehensive Analysis for the Transcriptional Organization of Stimuli Responses in Fibroblast-like Synoviocytes from Rheumatoid Arthritis Patients

Haruka Tsuchiya1, Shuji Sumitomo1, Kazuyoshi Ishigaki2, Akari Suzuki2, Yuta Kochi2, Mineto Ota1, Yumi Tsuchida1, Hiroshi Inui3, Shuji Taketomi3, Yuho Kadono4, Sakae Tanaka3, Keishi Fujio1 and Kazuhiko Yamamoto1,2, 1Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan, 3Department of Orthopaedic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 4Department of Orthopaedic Surgery, Graduate School of Medicine, Saitama Medical University, Saitama, Japan

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: cytokines, Fibroblasts, rheumatoid arthritis (RA) and transcriptional regulation

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Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:   Fibroblast-like synoviocyte (FLS) is expected to be a novel therapeutic target for rheumatoid arthritis (RA) because of their contribution to pathogenesis. FLS expresses matrix metalloproteinases, chemokines and cytokines in a response to various cytokines in affected joints, which leads bone and cartridge destruction, inflammatory cell recruitment and angiogenesis in pannus. The objective of this study is to investigate the transcriptional organization of stimuli responses and to clarify a character of RA-FLS.

Methods:   Synovium were obtained from RA (n = 21) and osteoarthritis (OA) patients (n = 23) who underwent joint replacement surgery with informed consent. Minced synovium were treated with collagenase and cultured in Dulbecco modified Eagle’s medium supplemented with 10% fetal bovine serum. At passage 2, FLS were isolated with removal of contaminating CD14 positive cells by magnetic-activated cell sorting. Purified FLS were stimulated with cytokines (TNF-α, IL-1β, IL-6/sIL-6R, IL-17A, IL-18, IFN-γ, IFN-α, TGF-β1 and combination of all 8 cytokines which simulated the mixture of stimuli in the joint) for 10 and 24 hours. Total RNA was extracted and libraries for RNA-sequence were prepared using TruSeq Stranded mRNA Library Prep kit (Illumina), and paired-end sequencing was performed using HiSeq 2500 (Illumina).

Results:   The overview of transcriptomes with multi-dimensional scaling plot revealed that there were conserved transcriptome differences between RA and OA-FLS for each stimulatory condition, although the fluctuation vector with each stimuli were similar between RA and OA-FLS. Through the pathway analysis, 12 transcriptional regulators and those downstream genes were supposed to be significantly upregulated in RA-FLS compared to OA-FLS. In particular, E2F transcription factor 6 (E2F6), heat shock factor protein 1 (HSF1), Lysine (K)-specific demethylase 5B (KDM5B), nuclear protein 1 (NUPR1), tumor protein P53 (TP53) were expected to affect the downstream gene expression in stimulatory conditions compared with non-stimulatory condition. Among 1468 downstream genes of these 5 transcriptional regulators, 26 genes related to RA genome-wide association study (GWAS) were detected. Notably, colony stimulating factor 2 (CSF2), cyclin-dependent kinase 2 (CDK2) and flap structure-specific endonuclease 1 (FEN1) were significantly differentially expressed gene not only in RA-FLS compared with OA-FLS, but also in cytokine-stimulated FLS compared with non-stimulatory condition. Furthermore, through the correlation analysis, CSF2 expression which was induced by certain cytokines (IL-1β, TNF-α, all cytokine mixture) was highly correlated with particular transcription factors (i.e. JUN, FOX, JUND).

Conclusion:   CSF2 was specifically expressed in RA-FLS and significantly expressed in the presence of stimulation. Although CSF2 locus was raised in RA GWAS, the expression quantitative trait loci (eQTL) effect for CSF2 gene has yet to be determined. Through comprehensive analysis, the mechanism for CSF2 expression and the pathway of RA-FLS specific transcription is expected to be elucidated.


Disclosure: H. Tsuchiya, None; S. Sumitomo, None; K. Ishigaki, Takeda, 2; A. Suzuki, Takeda, 2; Y. Kochi, Takeda, 2; M. Ota, None; Y. Tsuchida, None; H. Inui, None; S. Taketomi, None; Y. Kadono, None; S. Tanaka, None; K. Fujio, Bristol-Myers Squibb, 2,Chugai, 2,Takeda, 2,Daiichi-Sankyo, 7,MitsubishiTanabe, 7,Pfizer Inc, 7,Santen, 7,Eisai, 7,Taisho Toyama, 7,UCB., 7,Janssen Pharmaceutica Product, L.P., 7; K. Yamamoto, Bristol-Myers Squibb, 2,Takeda, 2,Chugai, 2,AbbVie, 7,Astellas, 7,Daiichi-Sankyo, 7,MitsubishiTanabe, 7,Pfizer Inc, 7,Sanofi, 7,Santen, 7,Teijin, 7,Boehringer Ingelheim, 7,Eisai, 7,Ono, 7,Taisho Toyama, 7,UCB., 7,ImmunoFuture, 7,Asahi Kasei, 7,Janssen Pharmaceutica Product, L.P., 7.

To cite this abstract in AMA style:

Tsuchiya H, Sumitomo S, Ishigaki K, Suzuki A, Kochi Y, Ota M, Tsuchida Y, Inui H, Taketomi S, Kadono Y, Tanaka S, Fujio K, Yamamoto K. The Comprehensive Analysis for the Transcriptional Organization of Stimuli Responses in Fibroblast-like Synoviocytes from Rheumatoid Arthritis Patients [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-comprehensive-analysis-for-the-transcriptional-organization-of-stimuli-responses-in-fibroblast-like-synoviocytes-from-rheumatoid-arthritis-patients/. Accessed May 17, 2022.
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