Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, China.
Department of Cariology and Endodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, Jiangsu 210008, China.
Eur J Pharmacol. 2019 May 15;851:144-150. doi: 10.1016/j.ejphar.2019.02.026. Epub 2019 Feb 15.
Periodontal disease is a bacterial infection-associated disease of the periodontal tissues characterized by the destruction of tooth-supporting structures, including alveolar bone. The ideal goal of periodontal therapy is the complete regeneration of alveolar bone in a healthy microenvironment free of infection. In this study, we found that berberine, a benzylisoquinoline plant alkaloid from Coptidis Rhizoma, strongly inhibited the growth of Porphyromonas gingivalis. Gingipain is the most important virulence factor of Porphyromonas gingivalis in the process of periodontal tissue destruction. Berberine also had an inhibitory effect on gingipain activity in a concentration dependent manner. Remarkably, berberine restored the downregulation of osteogenesis-related genes expression in bone mesenchymal stem cells (BMSCs) induced by Porphyromonas gingivalis infection, and significantly increased the expression of osteogenesis-related genes such as OSX, COLI, ALP, OCN and OPN compared to the control group. This results suggested that berberine may directly promote osteogenesis. Further in-vitro studies demonstrated that berberine statistically significantly promoted the osteogenic differentiation of BMSCs at concentrations of 1-10 μM. In the research on the mechanisms, we found that both total β-catenin and nuclear β-catenin accumulation were statistically significantly increased by berberine. And the transcriptional activity of β-catenin/TCF was about 2 folds higher than the control group. Furthermore, Wnt signalling specific inhibitor DKK-1 blocked the above effects of berberine. These demonstrated that Wnt/β-catenin signalling pathway was involved in the osteogenic differentiation induced by berberine. The antibacterial actions in combination with the promotion role in osteogenic differentiation position berberine as a prospective drug for periodontal tissue regeneration.
牙周病是一种与牙周组织细菌感染相关的疾病，其特征是牙齿支撑结构（包括牙槽骨）的破坏。牙周病治疗的理想目标是在无感染的健康微环境中，使牙槽骨完全再生。在这项研究中，我们发现小檗碱（黄连根茎中的一种苯并异喹啉植物生物碱）强烈抑制牙龈卟啉单胞菌的生长。牙龈蛋白酶是牙龈卟啉单胞菌在破坏牙周组织过程中最重要的毒力因子。小檗碱还以浓度依赖的方式抑制牙龈蛋白酶活性。值得注意的是，小檗碱恢复了牙龈卟啉单胞菌感染诱导的骨髓间充质干细胞（BMSCs）中骨生成相关基因表达的下调，并显著增加了骨生成相关基因（如 OSX、COLI、ALP、OCN 和 OPN）的表达，与对照组相比。这表明小檗碱可能直接促进成骨。进一步的体外研究表明，小檗碱在 1-10 μM 的浓度下显著促进 BMSCs 的成骨分化。在机制研究中，我们发现小檗碱使总β-catenin 和核β-catenin 积累均显著增加。β-catenin/TCF 的转录活性比对照组高约 2 倍。此外，Wnt 信号通路特异性抑制剂 DKK-1 阻断了小檗碱的上述作用。这些表明 Wnt/β-catenin 信号通路参与了小檗碱诱导的成骨分化。抗菌作用与促进成骨分化的作用使小檗碱成为牙周组织再生的有前途的药物。
