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Abstract Number: 1996

Bromodomain Inhibitor, I-BET762 Inhibits Production of Pro-inflammatory in Rheumatoid Arthritis Fibroblast-like Synoviocytes and Differentiation of Osteoclast

Ra Ham Kim1, Hyun Jung Yoo 2, Shin Eui Kang 3, Ji soo Park 4, Seon Uk Kim 5, Eun Young Lee 6, Jin Kyun Park 6 and Yeong-Wook Song 7, 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Repulbic of Korea, Seoul, Republic of Korea, 3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Republic of Korea, Seoul, Republic of Korea, 4Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea., Seoul, Republic of Korea, 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul National University, Seoul, Republic of Korea, 6Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Seoul, Republic of Korea, 7Seoul National University Hospital, Seoul, Republic of Korea

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Bromodomain, Epigenetics, osteoclastogenesis and cell biology, rheumatoid arthritis, synovium

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Session Information

Date: Tuesday, November 12, 2019

Session Title: RA – Etiology & Pathogenesis Poster II

Session Type: Poster Session (Tuesday)

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

Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by joint inflammation and bone destruction. The fibroblast-like synoviocyte(FLS) contributes to the pathogenesis of RA through cellular proliferation and production of cytokines or chemokines. Recently, blockade of the bromodomain and extra-terminal domain (BET) family protein was reported to be a potential therapeutic target by inhibiting epigenetic interaction between bromodomains and acetylated histones. This study aimed to investigate the effects of bromodomain-containing protein 4 (BRD4) inhibition on tumor necrosis factor (TNF)-α-stimulated RA-FLS and osteoclast using BRD4 inhibitor, I-BET762. 

Methods: RA-FLSs were treated with TNF-α in the presence of I-BET762 for 48 h. The cell viability and proliferation were measured after 24, 48, and 72 h in I-BET762-treated RA-FLS using CCK-8 colormetric assay. We then screened pro-inflammatory mediators by using the human inflammation antibody array. The levels of interleukin (IL)-6, IL-8 and CXCL-10 were measured in culture supernatants of TNF-α-stimulated RA-FLS by ELISA. Migrations were analyzed by the wound healing assay. We compared the expression of BRD2, BRD3 and BRD4 level by BRD4 specific inhibition in RA. Expression of c-Myc was detected by using Western blot. PBMC isolated from buffy coat were cultured with M-CSF and RANKL for 14 days in the presence or absence of I-BET762. Cells were stained with tartrate-resistant acid phosphatase (TRAP) and the number was counted by light microscopy. The ability of actin formation in osteoclast was evaluated by immunofluorecent stain.

Results: I-BET762 had no effect on cytotoxicity and proliferation of RA-FLS. I-BET762 reduced the secretion of IL-6, CXCL-10 and regulated upon activation, normal T cell expressed, and secreted (RANTES) from RA-FLS in the antibody array. Level of IL-6, IL-8 and CXCL-10 were significantly decreased after treatment with I-BET762 by ELISA. The number of migrated cells decreased in response to I-BET762 compared with the vehicle. The expression levels of BRD2, BRD3 and BRD4 proteins did not change with I-BET762. Expression of the target molecule, c-Myc, was decreased in I-BET762 treated RA-FLSs. TRAP-positive multinucleated (more than three nuclei) cells were reduced in a dose-dependent manner. The actin formation of podosome, actin belt and actin ring were inhibited in the presence of I-BET762.

Conclusion: Inhibition of BRD4 by I-BET762 led to down-regulation of pro-inflammatory mediators, migration and expression of c-Myc in RA-FLSs. The differentiation of osteoclast and resorption activity was inhibited by I-BET762. These data suggest that the I-BET762 may have anti-inflammatory properties and prevent bone loss in RA.


Disclosure: R. Kim, None; H. Yoo, None; S. Kang, None; J. Park, None; S. Kim, None; E. Lee, None; J. Park, None; Y. Song, Astellas Pharma, Inc., 9.

To cite this abstract in AMA style:

Kim R, Yoo H, Kang S, Park J, Kim S, Lee E, Park J, Song Y. Bromodomain Inhibitor, I-BET762 Inhibits Production of Pro-inflammatory in Rheumatoid Arthritis Fibroblast-like Synoviocytes and Differentiation of Osteoclast [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/bromodomain-inhibitor-i-bet762-inhibits-production-of-pro-inflammatory-in-rheumatoid-arthritis-fibroblast-like-synoviocytes-and-differentiation-of-osteoclast/. Accessed January 28, 2023.
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