School of Dentistry and Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Dent Res. 2013 Jul;92(7):629-34. doi: 10.1177/0022034513488139. Epub 2013 Apr 22.
Transforming growth factor β (TGFβ) is a key regulator associated with the pathogenesis of gingival overgrowth (GO). Connective tissue growth factor (CTGF/CCN2) is overexpressed in GO tissues. CCN2 promotes and sustains fibrosis initiated by TGFβ. Previous studies have shown that JNK and Smad3 activation is required for TGFβ-induced CCN2 expressions in human gingival fibroblasts (HGFs). In this study, we have found that Src is a major signaling mediator for TGFβ-induced CCN2 expressions in HGFs. Pre-treatment with 2 Src kinase inhibitors (PP2, Src inhibitor-1) significantly reduced TGFβ1-induced CCN2 synthesis and JNK and Smad3 activation in HGFs. These results suggest that Src is an upstream signaling transducer of JNK and Smad3 with respect to TGFβ1-stimulated CCN2 expression in HGFs. We further found that curcumin significantly abrogated the TGFβ1-induced CCN2 in HGFs by inhibiting the phosphorylations of Src, JNK, and Smad3. Furthermore, curcumin inhibited TGFβ1-induced HGF migration and α-SMA expression. Curcumin potentially qualifies as a useful agent for the control of GO.
转化生长因子 β（TGFβ）是与牙龈过度生长（GO）发病机制相关的关键调节因子。结缔组织生长因子（CTGF/CCN2）在 GO 组织中过度表达。CCN2 促进和维持 TGFβ 引发的纤维化。先前的研究表明，JNK 和 Smad3 的激活是 TGFβ 诱导人牙龈成纤维细胞（HGFs）中 CCN2 表达所必需的。在这项研究中，我们发现Src 是 TGFβ 诱导 HGFs 中 CCN2 表达的主要信号转导介质。用 2 种Src 激酶抑制剂（PP2、Src 抑制剂-1）预处理可显著降低 TGFβ1 诱导的 HGFs 中 CCN2 的合成以及 JNK 和 Smad3 的激活。这些结果表明，Src 是 JNK 和 Smad3 的上游信号转导物，与 TGFβ1 刺激 HGFs 中 CCN2 的表达有关。我们进一步发现姜黄素通过抑制 Src、JNK 和 Smad3 的磷酸化，显著抑制 TGFβ1 诱导的 HGFs 中 CCN2 的表达。此外，姜黄素抑制 TGFβ1 诱导的 HGF 迁移和α-SMA 表达。姜黄素可能是控制 GO 的有效药物。
