BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction
BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction
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BET 抑制剂 JQ1 阻止炎症和骨质破坏
DOI：
10.1177/0022034514534261
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发表时间：
2014-07-01
影响因子：
7.6
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Meng, S.;Zhang, L.;Chen, J.
BET蛋白是一组表观遗传调节因子，通过阅读乙酰化组蛋白尾巴和招募转录复合体来控制转录。它们被认为是许多不同疾病的潜在治疗靶点。一种新型的合成溴结构域和端外结构域(BET)抑制剂JQ1被证明可以抑制癌基因转录和炎症反应。本研究旨在探讨JQ1对实验性牙周炎炎症反应和骨破坏的影响。我们发现JQ1在体外显著抑制脂多糖(LPS)诱导的炎性细胞因子转录，包括白介素1β(IL-1β)、白介素6(IL-6)和肿瘤坏死因子α(TNF-α)，以及核因子kappaB配体受体激活剂(RANKL)诱导的破骨细胞标志物，如c-Fos、活化T细胞核因子、胞浆、钙调神经磷酸酶依赖性1(NFATc1)、抗酒石酸酸性磷酸酶(TRAP)和组织蛋白K。JQ1还抑制Toll样受体2/4(TLR2/4)的表达和核因子-kappa轻链增强子(nf-kappaB)的磷酸化和核转位。染色质免疫沉淀和定量聚合酶链式反应(ChIP-qPCR)显示，JQ1中和了BRD4在几个基因启动子区域的浓缩，包括核因子-kappa B、肿瘤坏死因子-α、c-Fos和NFATc1。在小鼠牙周炎模型中，全身性给药JQ1显著抑制了病变牙龈组织中炎症细胞因子的表达。由于牙周组织中破骨细胞的减少，JQ1治疗的小鼠的牙槽骨丢失得到缓解。这些史无前例的结果表明，BET抑制剂JQ1有望成为治疗牙周炎的新方法。
BET proteins are a group of epigenetic regulators controlling transcription through reading acetylated histone tails and recruiting transcription complexes. They are considered as potential therapeutic targets in many distinct diseases. A novel synthetic bromodomain and extraterminal domain (BET) inhibitor, JQ1, was proved to suppress oncogene transcription and inflammatory responses. The present study was aimed to investigate the effects of JQ1 on inflammatory response and bone destruction in experimental periodontitis. We found that JQ1 significantly suppressed lipopolysaccharide (LPS)-stimulated inflammatory cytokine transcription, including interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), as well as receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast markers, such as c-Fos, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K in vitro. JQ1 also inhibited toll-like receptors 2/4 (TLR2/4) expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) phosphorylation and nuclear translocation. Chromatin immunoprecipitation and quantitative polymerase chain reaction (ChIP-qPCR) revealed that JQ1 neutralized BRD4 enrichment at several gene promoter regions, including NF-kappa B, TNF-alpha, c-Fos, and NFATc1. In a murine periodontitis model, systemic administration of JQ1 significantly inhibited inflammatory cytokine expression in diseased gingival tissues. Alveolar bone loss was alleviated in JQ1-treated mice because of reduced osteoclasts in periodontal tissues. These unprecedented results suggest the BET inhibitor JQ1 as a prospective new approach for treating periodontitis.