School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan.
J Dent Res. 2015 Jul;94(7):976-82. doi: 10.1177/0022034515580986. Epub 2015 Apr 9.
Transforming growth factor β (TGFβ) plays a central role in the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF; or CCN2) is induced by TGFβ in human gingival fibroblasts (HGFs) and is overexpressed in GO tissues. CCN2 creates an environment favorable for fibrogenesis and is required for the maximal profibrotic effects of TGFβ. We previously showed that Src, JNK, and Smad3 mediate TGFβ1-induced CCN2 protein expression in HGFs. Moreover, Src is an upstream signaling transducer of JNK and Smad3. Recent studies suggested that NADPH oxidase (NOX)-dependent redox mechanisms are involved in mediating the profibrotic effects of TGFβ. In this study, we demonstrated that TGFβ1 upregulated NOX4 protein expression and increased reactive oxygen species (ROS) production in HGFs. Genetic or pharmacologic targeting of NOX4 abrogated TGFβ1-induced ROS production; Src, JNK, and Smad3 activation; and CCN2 and type I collagen protein expression in HGFs. Our results indicated that NOX4-derived ROS play pivotal roles in activating Src kinase activity leading to the activation of canonical (Smad3) and noncanonical (JNK) cascades that cooperate to attain maximum CCN2 expression. Furthermore, we demonstrated that curcumin significantly inhibited the TGFβ1-induced NOX4 protein expression in HGFs. Curcumin potentially qualifies as an agent to control GO by suppressing TGFβ1-induced NOX4 expression in HGFs.
转化生长因子 β（TGFβ）在牙龈过度生长（GO）的发病机制中起核心作用。结缔组织生长因子（CTGF；或 CCN2）在人牙龈成纤维细胞（HGFs）中由 TGFβ诱导，并在 GO 组织中过度表达。CCN2 创造了有利于纤维化的环境，是 TGFβ 最大致纤维化作用所必需的。我们之前表明，Src、JNK 和 Smad3 介导 TGFβ1 诱导的 HGFs 中 CCN2 蛋白表达。此外，Src 是 JNK 和 Smad3 的上游信号转导物。最近的研究表明，NADPH 氧化酶（NOX）依赖性氧化还原机制参与介导 TGFβ 的致纤维化作用。在这项研究中，我们证明 TGFβ1 上调了 HGFs 中的 NOX4 蛋白表达并增加了活性氧（ROS）的产生。NOX4 的遗传或药物靶向消除了 TGFβ1 诱导的 ROS 产生；Src、JNK 和 Smad3 的激活；以及 HGFs 中的 CCN2 和 I 型胶原蛋白表达。我们的结果表明，NOX4 衍生的 ROS 在激活 Src 激酶活性中起关键作用，从而激活经典（Smad3）和非经典（JNK）级联反应，从而协同实现 CCN2 表达的最大化。此外，我们证明姜黄素可显著抑制 TGFβ1 诱导的 HGFs 中 NOX4 蛋白表达。姜黄素有可能通过抑制 HGFs 中 TGFβ1 诱导的 NOX4 表达来控制 GO。
