Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Department of Periodontics and Oral Medicine, University of Mansoura Faculty of Dentistry, Mansoura, Egypt.
Cell Microbiol. 2018 Apr;20(4). doi: 10.1111/cmi.12815. Epub 2018 Jan 8.
Host-derived matrix metalloproteinases (MMPs) and bacterial proteases mediate destruction of extracellular matrices and supporting alveolar bone in periodontitis. The Treponema denticola dentilisin protease induces MMP-2 expression and activation in periodontal ligament (PDL) cells, and dentilisin-mediated activation of pro-MMP-2 is required for cellular fibronectin degradation. Here, we report that T. denticola regulates MMP-2 expression through epigenetic modifications in the periodontium. PDL cells were treated with epigenetic enzyme inhibitors before or after T. denticola challenge. Fibronectin fragmentation, MMP-2 expression, and activation were assessed by immunoblot, zymography, and qRT-PCR, respectively. Chromatin modification enzyme expression in T. denticola-challenged PDL cells and periodontal tissues were evaluated using gene arrays. Several classes of epigenetic enzymes showed significant alterations in transcription in diseased tissue and T. denticola-challenged PDL cells. T. denticola-mediated MMP-2 expression and activation were significantly reduced in PDL cells treated with inhibitors of aurora kinases and histone deacetylases. In contrast, DNA methyltransferase inhibitors had little effect, and inhibitors of histone acetyltransferases, methyltransferases, and demethylases exacerbated T. denticola-mediated MMP-2 expression and activation. Chronic epigenetic changes in periodontal tissues mediated by T. denticola or other oral microbes may contribute to the limited success of conventional treatment of chronic periodontitis and may be amenable to therapeutic reversal.
宿主来源的基质金属蛋白酶 (MMPs) 和细菌蛋白酶介导牙周炎中细胞外基质和支持性牙槽骨的破坏。牙龈卟啉单胞菌的牙龈蛋白酶诱导牙周韧带 (PDL) 细胞中 MMP-2 的表达和激活，并且牙龈蛋白酶介导的 pro-MMP-2 激活是细胞纤维连接蛋白降解所必需的。在这里，我们报告了 T. denticola 通过牙周组织中的表观遗传修饰来调节 MMP-2 的表达。在 T. denticola 挑战之前或之后，用表观遗传酶抑制剂处理 PDL 细胞。通过免疫印迹、酶谱分析和 qRT-PCR 分别评估纤维连接蛋白片段化、MMP-2 表达和激活。使用基因芯片评估 T. denticola 挑战的 PDL 细胞和牙周组织中染色质修饰酶的表达。几种表观遗传酶类在患病组织和 T. denticola 挑战的 PDL 细胞中的转录水平发生了显著改变。在用 Aurora 激酶和组蛋白去乙酰化酶抑制剂处理的 PDL 细胞中，T. denticola 介导的 MMP-2 表达和激活显著降低。相比之下，DNA 甲基转移酶抑制剂的作用很小，而组蛋白乙酰转移酶、甲基转移酶和去甲基酶抑制剂则加剧了 T. denticola 介导的 MMP-2 表达和激活。T. denticola 或其他口腔微生物介导的牙周组织中的慢性表观遗传变化可能导致慢性牙周炎的常规治疗效果有限，并且可能适合治疗逆转。
