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<p>The BRD and extra-terminal domain (BET) family of proteins was inhibited using I-BET762, a small molecule inhibitor, which mimics interaction with acetylated lysin residue in BET protein. We explored the roles of the bromodomain (BRD) of chromatin adapators in regulating synovial inflammation in rheumatoid arthritis (RA). The expression levels of bromodomain proteins, c-Myc, and the components of the MAPK and NF-<i>κ</i>B signaling pathways were detected by western blot. The BRD3, BRD4, and c-Myc expression were suppressed by I-BET762-treated RA-FLS. I-BET762 inhibited the phosphorylation of p38 MAPK and NF-<i>κ</i>B signaling pathways. Moreover, secretion levels of pro-inflammatory mediators (IL-6 and IL-8), chemokine (CXCL-10), and MMP-1 and -3 significantly decreased after I-BET762 treatment. Cell migration and invasion were also reduced in response to I-BET762 treatment. I-BET762 treatment concurrently inhibited p38 MAPK and NF-<i>κ</i>B, thereby suppressing the inflammatory properties of RA-FLS. In osteoclastogenesis, TRAP-positive multi-nucleated cells were reduced by I-BET762 in a dose-dependent manner. The actin ring formation of RANKL-induced osteoclast was inhibited in the presence of I-BET762. I-BET762 down-regulated pro-inflammatory, matrix-degrading, chemo-attractive properties in RA-FLS and, bone resorption in osteoclast. These data suggest that I-BET762 inhibit synovial inflammation and bone resorption in RA. In vivo animal experiment may be needed for confirmation.</p>

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Epigenetic suppression of synovial inflammation and osteoclast differentiation in rheumatoid arthritis by I-BET762

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月23日

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  • Ra Ham Kim,
  • Sang Un Choi,
  • Yeong Wook Song

摘要

The BRD and extra-terminal domain (BET) family of proteins was inhibited using I-BET762, a small molecule inhibitor, which mimics interaction with acetylated lysin residue in BET protein. We explored the roles of the bromodomain (BRD) of chromatin adapators in regulating synovial inflammation in rheumatoid arthritis (RA). The expression levels of bromodomain proteins, c-Myc, and the components of the MAPK and NF-κB signaling pathways were detected by western blot. The BRD3, BRD4, and c-Myc expression were suppressed by I-BET762-treated RA-FLS. I-BET762 inhibited the phosphorylation of p38 MAPK and NF-κB signaling pathways. Moreover, secretion levels of pro-inflammatory mediators (IL-6 and IL-8), chemokine (CXCL-10), and MMP-1 and -3 significantly decreased after I-BET762 treatment. Cell migration and invasion were also reduced in response to I-BET762 treatment. I-BET762 treatment concurrently inhibited p38 MAPK and NF-κB, thereby suppressing the inflammatory properties of RA-FLS. In osteoclastogenesis, TRAP-positive multi-nucleated cells were reduced by I-BET762 in a dose-dependent manner. The actin ring formation of RANKL-induced osteoclast was inhibited in the presence of I-BET762. I-BET762 down-regulated pro-inflammatory, matrix-degrading, chemo-attractive properties in RA-FLS and, bone resorption in osteoclast. These data suggest that I-BET762 inhibit synovial inflammation and bone resorption in RA. In vivo animal experiment may be needed for confirmation.