Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Bone Tumour Institution, Shanghai 201620, China.
Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3001-3015. doi: 10.1016/j.bbadis.2017.08.009. Epub 2017 Aug 24.
Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1β-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA.
骨关节炎（OA）传统上被定义为一种非炎症性疾病。最近，许多研究表明 OA 也具有炎症成分。BRD4 是 Bromodomain 和 Extra-Terminal Domain 家族的成员，已成为一些慢性炎症性疾病的重要调节剂。BRD4 的拮抗剂 JQ1 调节几种基因的转录。我们的研究表明 BRD4 在 OA 关节软骨中上调。BRD4 抑制减轻软骨细胞的炎症和分解代谢，并抑制 NF-κB 信号通路的激活。此外，BRD4 抑制消除了高迁移率族蛋白 B1（HMGB1）的转录活性。我们确定 HMGB1 是 BRD4 的直接靶标。BRD4 的遗传和药理学抑制抑制了 IL-1β诱导的 HMGB1 的表达和易位。染色质免疫沉淀（ChIP）显示 BRD4 在 HMGB1 上游非启动子区域周围富集，用 JQ1 处理后减少。最后，苏木精和伊红及番红 O/快绿染色表明 JQ1 减轻了前交叉韧带横断小鼠的软骨破坏，而没有明显的毒性作用。这些研究强调了 BRD4 在 OA 的慢性炎症反应中的重要性，据我们所知，这是首次报道这一发现，并表明 BRD4 可能是治疗 OA 的一个新的潜在治疗靶点。
