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Abstract Number: 38

Autophagy Receptor Optineurin in Synovial Fibroblasts Plays a Protective Role Against Joint Destruction in Rheumatoid Arthritis

Wen Shi Lee1, Masaru Kato 1, Eri Sugawara 1, Michihiro Kono 1, Yuki Kudo 2, Michihito Kono 3, Yuichiro Fujieda 1, Toshiyuki Bohgaki 1, Olga Amengual 1, Kenji Oku 1, Shinsuke Yasuda 1 and Tatsuya Atsumi 4, 1Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan, 2Hokkaido University Graduate School of Medicine, Sapporo, Japan, 3Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan, 4Hokkaido University, Sapporo, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: joint destruction and autophagy proteins, pathogenesis, rheumatoid arthritis

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Session Information

Date: Sunday, November 10, 2019

Session Title: RA – Etiology & Pathogenesis Poster I

Session Type: Poster Session (Sunday)

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

Background/Purpose: Joint destructions progress throughout the course of rheumatoid arthritis (RA) without complete remission. Optineurin (OPTN) is an autophagy receptor with multiple functions related to homeostasis of cells and has been reported to negatively regulate osteoclast differentiation in vivo. However, the role of OPTN in RA, especially in joint destruction, has been unclear. In this study, we clarify the role of OPTN in the pathogenesis of joint destructions in RA using synovial fibroblasts (RASFs).

Methods: RASFs were obtained from RA patients who fulfilled the ACR 2010 criteria during the knee replacement surgery. RASFs with passages of 4 to 8 were used in this study. RASFs were incubated with pro-inflammatory cytokines and the expression of OPTN was analyzed using quantitative realtime PCR (RT-qPCR) and western blot. RASFs were transfected with siRNA targeting OPTN and the downregulated efficacy was confirmed by RT-qPCR and western blot. The expression of RANKL and osteoprotegerin (OPG) on OPTN-reduced RASFs were analyzed by flow cytometry and RT-qPCR after treatment with TNF-a or IFN-g. CD14+ monocytes isolated from healthy subjects were cocultured with OPTN-reduced RASFs or control RASFs in the presence of M-CSF. RANKL+M-CSF added in cocultured cells were used as positive control. Cocultured cells were stained with Tartrate-Resistant Acid Phosphatase (TRAP). TRAP+ cells with number of nuclei≥3 were considered as osteoclasts. Protein levels of IkBa were analyzed to evaluate the activation of NF-kB signaling. RNA sequencing was performed to analyze further pro-inflammatory/pro-destructive genes regulated by OPTN knockdown. Data within a group were compared using Student’s unpaired t-test and data between groups were compared using the analysis of variance (GraphPad Prism). Differences were considered significant if p< 0.05.

Results: OPTN levels were upregulated after TNF-a or IFN-g stimulation at both mRNA and protein levels (n = 5, p< 0.05). The cell surface expression of RANKL was significantly increased following treatment with TNF-a or IFN-g and the effect was further pronounced in OPTN-reduced RASFs compared with that in control RASFs (n = 5, p< 0.05). The mRNA levels of RANKL were also increased in OPTN-reduced RASFs (n = 5, p< 0.05) while OPG levels remained unchanged. CD14+ monocytes cocultured with OPTN-reduced RASFs differentiated more into TRAP+ multinucleated cells (osteoclasts) compared to those cocultured with control RASFs (n = 4, p< 0.05). IkBa degradation following TNF-a treatment was prolonged in OPTN-reduced RASFs. RNA sequencing detected dysregulation of genes related to cartilage degradation, joint inflammation and bone formation, including MMP-3, CHST15, HAS1 and GATA-3, and the results were confirmed by RT-qPCR.

Conclusion: OPTN may play a protective role in RA with its upregulation when immersing with pro-inflammatory cytokines. Absence of OPTN might worsen RA by generating joint destructive state including increased RANKL expression on RASFs and subsequent osteoclast differentiation.


ACR figure


Disclosure: W. Lee, None; M. Kato, None; E. Sugawara, None; M. Kono, None; Y. Kudo, None; M. Kono, None; Y. Fujieda, None; T. Bohgaki, None; O. Amengual, None; K. Oku, None; S. Yasuda, None; T. Atsumi, AbbVie, 5, 8, Abbvie, 5, 8, Asahi Kasei Pharma Corporation, 8, Astellas Pharma, 8, 9, Astellas Pharma Inc, 8, AstraZeneca, 5, AstraZeneca plc, 5, 8, Bayer Yakuhin, 8, Bayer Yakuhin, Ltd., 8, Bristol-Myers Squibb, 8, 9, Chugai Pharmaceutical Co Ltd, 8, Chugai Pharmaceutical Co., 8, 9, Daiichi Sankyo, 8, 9, Daiichi Sankyo Co Ltd, 8, Eisai Co., Ltd, 8, Eli Lilly and Company, 8, 9, Eli Lilly Japan KK, 8, Elsai Co Ltd, 8, Gilead Sciences, 8, Gilead Sciences, Inc., 8, MEDICAL & BIOLOGICAL LABORATORIES CO., 5, Medical and Biological Laboratories Co Ltd, 5, Mitsubishi Tanabe Pharma, 8, 9, Nippon Shinyaku Co., 8, Novartis, 5, Novartis Pharma KK, 5, Ono Pharmaceutical, 5, ONO Pharmaceutical Co Ltd, 5, Otsuka Pharmaceutical, 8, Pfizer, 5, 9, Pfizer Inc, 5, 8, Sanofi, 9, Takeda Pharmaceutical Company, 8, Takeda Pharmaceuticals, 8.

To cite this abstract in AMA style:

Lee W, Kato M, Sugawara E, Kono M, Kudo Y, Kono M, Fujieda Y, Bohgaki T, Amengual O, Oku K, Yasuda S, Atsumi T. Autophagy Receptor Optineurin in Synovial Fibroblasts Plays a Protective Role Against Joint Destruction in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/autophagy-receptor-optineurin-in-synovial-fibroblasts-plays-a-protective-role-against-joint-destruction-in-rheumatoid-arthritis/. Accessed August 19, 2022.
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