Negative Regulation of Human Osteoclastogenesis

描述（由申请人提供）：牙周炎是一种慢性感染性/炎症性疾病，其中口腔生物膜/牙菌斑中存在的细菌驱动炎症状态，导致牙周软组织和牙槽骨的重塑和破坏失调。本申请将集中在炎症性骨吸收过程中抑制破骨细胞生成的机制。响应于致病性口腔细菌的细胞活化和炎症介质产生由识别保守微生物分子的“模式识别受体”介导。其中最重要的模式识别受体是Toll样受体2（TLR 2）和TLR 4，它们参与驱动牙周炎中的炎性骨吸收。在激活炎症的同时，TLR诱导有效的稳态机制以限制炎症的强度，从而限制相关的组织损伤。牙周炎的炎症程度和相关的骨丢失率是由炎症因子与反馈和体内平衡机制的相对效力之间的平衡决定的，反馈和体内平衡机制对抗炎症和骨吸收，并促进愈合。因此，疾病进展是相对无效的反馈抑制的证据，其不能抑制炎症和骨吸收，与在炎症的生理消退期间或在疾病的静止期期间发生的有效稳态调节相反。我们的总体假设是，增强生理稳态机制是一种有效的方法，以限制骨吸收与炎症。因此，我们已经开始了研究，以了解在炎症环境中，如牙周病，抑制破骨细胞形成的分子机制。我们已经发现，IL-10，一种由TLR诱导并在牙周炎中广泛表达的原型负调节因子，通过抑制RANK和TREM-2（对破骨细胞生成重要的关键受体）的信号传导来抑制破骨细胞生成。此外，我们发现TLR通过抑制破骨细胞前体发育过程中RANK和TREM-2的表达直接抑制破骨细胞前体的形成。有趣的是，我们的研究结果揭示了人类和小鼠破骨细胞生成调控之间的定性和定量差异，包括TREM-2的差异调控，这可能有助于解释骨重建调控的物种差异。在本申请中，我们将研究IL-10和TLR抑制人破骨细胞生成的抑制/稳态途径和分子机制。我们将使用与牙周炎发病机制直接相关的人类系统，并可能揭示在小鼠系统中不明显的机制。我们预期我们的研究将产生对内环境调节的深入了解，可用于治疗干预，以抑制牙周炎相关的牙槽骨吸收。项目简介：牙周炎是一种口腔细菌引起的炎症，破坏牙齿的牙科疾病。在这个应用程序中，我们将调查机制，抑制破骨细胞，破坏牙周炎的牙骨细胞。我们预计，我们的研究将产生的见解，可用于治疗干预，以抑制与牙周炎相关的骨和牙齿破坏。

DESCRIPTION (provided by applicant): Periodontitis is a chronic infectious/inflammatory disease in which bacteria present in oral biofilm/dental plaque drive an inflammatory state leading to dysregulated remodeling and destruction of periodontal soft tissues and alveolar bone. This application will focus on mechanisms of inhibition of the generation of osteoclasts during inflammatory bone resorption. Cell activation and inflammatory mediator production in response to pathogenic oral bacteria is mediated by `pattern recognition receptors' that recognize conserved microbial molecules. Among the most important pattern recognition receptors are Toll like receptors 2 (TLR2) and TLR4 that have been implicated in driving inflammatory bone resorption in periodontitis. At the same time as they activate inflammation, TLRs induce potent homeostatic mechanisms to limit the intensity of inflammation and thus limit associated tissue damage. The extent of inflammation and the rate of associated bone loss in periodontitis are determined by the balance between inflammatory factors and the relative potency of feedback and homeostatic mechanisms that oppose inflammation and bone resorption, and promote healing. Thus, disease progression is evidence of relatively ineffective feedback inhibition that is not able to restrain inflammation and bone resorption, in contrast to effective homeostatic regulation that occurs during physiological resolution of inflammation or during quiescent phases of disease. Our overarching hypothesis is that augmenting physiological homeostatic mechanisms represents an effective approach to limiting bone resorption associated with inflammation. Therefore, we have initiated studies to understand molecular mechanisms that restrain osteoclast formation in an inflammatory setting such as periodontal disease. We have found that IL-10, a prototypic negative regulator that is induced by TLRs and widely expressed in periodontitis, suppresses osteoclastogenesis by inhibiting signaling by RANK and TREM-2, key receptors important for osteoclastogenesis. In addition, we found that TLRs directly suppress the formation of osteoclast precursors by inhibiting RANK and TREM-2 expression during development of osteoclast precursors. Interestingly, our results revealed qualitative and quantitative differences between the regulation of human and murine osteoclastogenesis, including differential regulation of TREM-2, that may help explain species differences in regulation of bone remodeling. In this application, we will investigate inhibitory/homeostatic pathways and molecular mechanisms by which IL-10 and TLRs inhibit human osteoclastogenesis. We will use human systems that are directly relevant for periodontitis pathogenesis and may reveal mechanisms that are not readily apparent in murine systems. We anticipate that our studies will yield insights into homeostatic regulation that can be exploited for therapeutic interventions to suppress alveolar bone resorption associated with periodontitis. Project Narrative: Periodontitis is a dental disease in which oral bacteria cause inflammation that destroys teeth. In this application we will investigate mechanisms that inhibit osteoclasts, the cells that destroy tooth bone in periodontitis. We anticipate that our studies will yield insights that can be exploited for therapeutic interventions to suppress the bone and tooth destruction associated with periodontitis.