Roles for lymphocyte RANKL in periodontal complications of type 2 diabetes

牙周炎加剧了肥胖相关的2型糖尿病(T2D)的炎症，与血糖水平低下有关 控制，并增加T2D发病率。迫切需要新的策略来应对牙周来源 感染和由此导致的炎症，这两种疾病对标准治疗都是无效的 T2D。然而，牙周炎和T2D之间的关系的潜在机制仍然很差。 理解，阻碍临床进展。牙周炎和T2D之间的一个统一联系是改变的B细胞 功能，以及Barbara Nikolajczyk博士和Thomas Van Dyke博士最近的合作工作表明 B细胞中与T2D相关的变化会促进牙周炎。我们的研究进一步表明T细胞不能驱动 尽管有证据表明T细胞促进牙周炎，但T2D患者的慢性牙周炎患者没有B细胞 在瘦身的主人身上。综上所述，这些发现支持B细胞支持T2D增强的模型 牙周炎，而T细胞在牙周炎中占主导地位。B细胞和T细胞都是主要的来源 核因子kappa-B受体激活剂配体(RANKL)，破骨细胞生成的关键驱动因素，以及 牙周骨丢失。肥胖/T2D增加RANKL的造血细胞产量，很可能是通过 增加一些细胞因子(肿瘤坏死因子α、白介素1β和白介素6)的浓度，以推动RANKL的产生。 这些数据，加上我们的证明，B细胞是T2D增强的破骨细胞形成所必需的 和牙周炎，支持我们的中心假设：T2D细胞因子特异性地上调B细胞RANKL功能， 它独特地加强了T2D的牙周并发症。需要明确的分析来填补关键的 肥胖相关的T2D如何影响淋巴细胞RANKL诱导和功能的知识差距，以及 与瘦宿主相比，破骨细胞RANKL的细胞来源在T2D上是否不同。我们将利用损失- 以及在标准的T2D小鼠模型中的功能获得方法，结合慢性前列腺癌的标准模型 牙周炎，研究T2D-增强型牙周病的发展。我们将补充疾病 通过分析患有T2D的人的牙龈对小鼠进行病因学研究，以质疑其机制基础 慢性牙周炎。该策略将确定T2D强化的早期和慢性阶段的驱动因素 牙周炎达到我们的长期目标：找出促进牙周炎的关键因素在T2D中进行比较 对非T2D受试者，从而为未来的研究确定药物靶点。

Periodontitis fuels the inflammation of obesity-associated type 2 diabetes (T2D), associates with poor glycemic control, and increases T2D morbidity. New strategies are critically needed to counter sources of periodontal infection and the resulting inflammation, both of which are refractory to standard treatments in people with T2D. However, mechanisms underlying the relationship between periodontitis and T2D remain poorly understood, impeding clinical progress. One unifying link between periodontitis and T2D is altered B cell function, and recent collaborative work between Drs. Barbara Nikolajczyk and Thomas Van Dyke showed that T2D-associated changes in B cells promote periodontitis. Our work further indicates that T cells cannot drive chronic periodontitis in T2D hosts in the absence of B cells, despite evidence that T cells promote periodontitis in lean hosts. Taken together, these findings support a model in which B cells support T2D-potentiated periodontitis, while T cells dominate periodontitis in leans. Both B cells and T cells are major sources of receptor activator of nuclear factor kappa-B ligand (RANKL), a key driver of osteoclastogenesis and periodontal bone loss. Obesity/T2D increases hematopoietic cell production of RANKL, most likely through increasing concentrations of a number of cytokines (TNFα, IL-1β and IL-6) known to drive RANKL production. These data, together with our demonstration that B cells are required for T2D-potentiated osteoclastogenesis and periodontitis, support our central hypothesis: T2D cytokines specifically up regulate B cell RANKL function, which uniquely potentiates periodontal complications of T2D. Definitive analyses are needed to fill the critical gaps in knowledge of how obesity-associated T2D impacts lymphocyte RANKL induction and function, and whether cellular sources of osteoclastogenic RANKL differ in T2D compared to lean hosts. We will use loss- and gain-of-function approaches in a standard mouse model of T2D, coupled with a standard model of chronic periodontitis, to study development of T2D-potentiated periodontal disease. We will complement the disease etiology work in mice with analysis of gingiva from people with T2D to query mechanistic underpinnings of chronic periodontitis. This strategy will identify drivers of both early and chronic phases of T2D-potentiated periodontitis to meet our long-term objective: to identify key factors that promote periodontitis in T2D compared to non-T2D subjects, and thereby pinpoint drug targets for future studies.