Development of novel therapeutic approach for the prevention of alveolar bone destruction and atherosclerosis through the regulation of Wnt signaling

核因子kappaB受体激活剂(RANKL)促进破骨细胞分化，骨保护素(OPG)抑制破骨细胞生成。OPG基因缺陷小鼠表现出严重的骨化和动脉粥样硬化。WNT信号调节细胞分化和/或增殖，WNT信号的激活刺激OPG的表达。本研究的目的是检测RANKL和OPG在牙周炎和动脉粥样硬化病变中的表达，并探讨牙周感染在动脉粥样硬化中的作用。此外，我们还研究了Wnt信号对OPG表达的影响，为牙周炎和动脉粥样硬化的治疗提供可能的途径。目前的研究表明RANKL在牙周炎组织和腹主动脉瘤(AAA)组织中的表达增强。在AAA组织中，牙周病原菌的检出频率较高，而在健康牙周组织中则完全缺失。牙周病细菌内毒素可刺激血管平滑肌细胞RANKL的表达，RANKL可增强血管平滑肌细胞的基质金属蛋白酶的表达。这些结果表明，RANKL的表达不仅增强了破骨细胞的生成，而且还促进了AAA的损伤。通过siRNA抑制Wnt信号可以抑制OPG在不同细胞中的表达。姜黄素可增强OPG在不同细胞类型中的表达，提示姜黄素可能抑制牙周炎和AAA中RANKL的表达。这些结果提示，Wnt信号的调节可能抑制牙周炎和AAA。

Receptor activator of NF kappa B Ligand (RANKL) stimulates osteoclast differentiation, and osteoprotegerin (OPG) suppress the osteoclastogenesis. The OPG deficient mice showed severe osteopetrosis and atherosclerosis. The WNT signaling regulates cell differentiation and/or proliferation, and the activation of WNT signaling stimulates OPG expression. The purpose of this study was to examine the RANKL and OPG expression in periodontitis and atherosclerosis lesions, and evaluate the roles of periodontal infection on atherosclerosis. In addition, effects of Wnt signaling on OPG expression were also examined for the possible therapeutic approach against periodontitis and atherosclerosis. Present study showed that RANKL expression was augmented in periodontitis tissue and abdominal aortic aneurisms (AAA) tissue. In AAA tissues, periodontopathic bacteria were frequently detected, but they were completely absent in the healthy tissues. LPS from periodontopathic bacteria stimulated RANKL expression and RANKL augment MMP expression in vascular smooth muscle cells in vitro. These results suggest that RANKL expression augmented not only osteoclastogenesis, but also AAA lesion. Suppression of Wnt signaling by siRNA suppressed OPG expression in various cells. Curcumin augmented OPG expression in various cell types, suggesting that they might suppress RANKL expression in periodontitis and AAA. These results suggested that regulation of Wnt signaling might suppress periodontitis and AAA.