Periodontal infections and stem cell mobilization in atherosclerosis

牙周炎与心血管疾病密切相关。然而，基本的共同途径仍然没有完全被理解。血管健康是由健康的内皮维持的，而健康的内皮部分可以通过循环内皮再生细胞(例如Sca1+/flk1+祖细胞)再生。内皮细胞损伤后内皮再生受损与动脉粥样硬化病变的发生发展密切相关。我们已经证明，动脉粥样硬化倾向于载脂蛋白E缺陷小鼠的实验性牙周炎会导致外周血中有缺陷的祖细胞动员。从机制上讲，破骨细胞的激活是由核因子受体激活剂ĸB配体(RANKL)介导的，与祖细胞动员有关，而作为RANKL的诱骗受体的骨保护素(OPG)通过增加成骨作用来触发干细胞在骨髓中的扩张和滞留。我们发现牙周感染与随之而来的OPG增加和RANKL/OPG比率降低有关--与牙周组织中的情况相反。有趣的是，OPG是动脉粥样硬化的一个公认的替代标志物，并预测心血管死亡率。因此，牙周感染引起的骨髓细胞动员的改变可能构成动脉粥样硬化的一个新的机制联系。在此，我们建议揭示牙周感染影响骨髓细胞动员的确切机制，并探讨慢性牙周感染中动员减少的功能相关性。

Periodontitis has been closely connected to cardiovascular disease. However, the underlying common pathways remain incompletely understood. Vascular health is maintained by healthy endothelium that can in parts be regenerated by circulating endothelial-regenerating cells (e.g. Sca1+/flk1+ progenitors). Impaired endothelial regeneration after endothelial cell damage is closely connected to the development of atherosclerotic lesions. We have demonstrated that experimental periodontitis in atherosclerosis-prone ApoE-deficient mice leads to defective progenitor cell mobilization into peripheral blood (PB). Mechanistically, osteoclast activation, mediated by receptor activator of nuclear factor ĸB ligand (RANKL), is associated with progenitor cell mobilization whilst osteoprotegerin (OPG), a decoy receptor for RANKL, triggers stem cell expansion and retention within the BM via increased osteogenesis. We showed that periodontal infections are associated with a concomitant increase in OPG and a decreased RANKL/OPG ratio – inverse of the situation in the periodontal tissues. Interestingly, OPG is an established surrogate marker of atherosclerosis and predicts cardiovascular mortality. Therefore, the alteration of BM cell mobilization by periodontal infections may constitute a novel mechanistic link to atherosclerosis.We herein propose to elicit the exact mechanisms by which periodontal infections influence cell mobilization from the bone marrow, and to explore the functional relevance of decreased mobilization in chronic periodontal infections.