Negative Regulation of Human Osteoclastogenesis

人类破骨细胞生成的负调控

基本信息

批准号：
8089430
负责人：
Lionel B Ivashkiv
金额：
$ 42.01万
依托单位：
HOSPITAL FOR SPECIAL SURGERY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089430
关键词：
3&apos Untranslated Regions Automobile Driving Bacteria Bone Resorption Bone remodeling Cell Lineage Cell Wall Cells Chronic Defect Dental Plaque Development Disease Disease Progression Epigenetic Process Equilibrium Feedback Generations Genetic Transcription Healed Human ITAM Immune Inflammation Inflammation Mediators Inflammatory Interleukin-10 Invaded Lipopolysaccharides Mediating Messenger RNA MicroRNAs Molecular Morbidity - disease rate Mus Mutation Myelogenous Nucleic Acids Osteoclasts Pathogenesis Pathway interactions Patients Pattern recognition receptor Periodontal Diseases Periodontitis Phase Physiological Porphyromonas gingivalis Post-Transcriptional Regulation Production Proteins Regulation Relative (related person)Resolution Signal Transduction System TLR4 gene Testing Therapeutic Intervention Time Tissues Toll-Like Receptor 2 Tooth Diseases Tooth structure alveolar bone base bone bone loss chromatin modification cytokine healing inflammatory bone resorption insight microbial novel therapeutic intervention oral bacteria oral biofilm osteoclastogenesis pathogenic bacteria receptor response soft tissue species difference

项目摘要

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.

描述（由申请人提供）：牙周炎是一种慢性传染性/炎症性疾病，其中细菌存在于口服生物膜/牙菌斑中的细菌驱动炎症状态，导致牙周软组织和肺泡骨的重塑和破坏。该应用将集中在炎症骨吸收期间抑制破骨细胞产生的机制。细胞活化和炎症介质对致病性口服细菌的产生是由识别保守的微生物分子的“模式识别受体”介导的。在最重要的模式识别受体中，包括受体2（TLR2）和TLR4的收费，这与牙周炎中的炎症骨吸收有关。在激活炎症的同时，TLR会诱导有效的稳态机制来限制炎症的强度，从而限制相关的组织损伤。炎症的程度和牙周炎中相关骨质流失的速度取决于炎症因子之间的平衡以及反馈和稳态机制的相对效力，反对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，而反馈抑制作用是无法抑制炎症和骨吸收的证据，与在炎症的生理解析或疾病静止阶段发生的有效稳态调节相比。我们的总体假设是，增强生理稳态机制是限制与炎症相关的骨吸收的有效方法。因此，我们已经开始研究，以了解在炎症环境（例如牙周疾病）中抑制破骨细胞形成的分子机制。我们发现，IL-10是由TLR诱导并在牙周炎中广泛表达的原型负调节剂，通过抑制秩和Trem-2的信号传导来抑制破骨细胞构成，这对骨质质构成很重要。此外，我们发现TLR通过在破骨细胞前体的发育过程中抑制秩和trem-2表达来直接抑制破骨细胞前体的形成。有趣的是，我们的结果揭示了人和鼠骨碎片发生的调节之间的定性和定量差异，包括trem-2的差异调节，这可能有助于解释物种在骨重塑调节中的物种差异。在此应用中，我们将研究IL-10和TLR抑制人骨构成发生的抑制/稳态途径和分子机制。我们将使用与牙周炎发病机理直接相关的人类系统，并可能揭示在鼠系统中不易明显的机制。我们预计我们的研究将产生对稳态调节的见解，可以利用这些调节进行治疗干预措施，以抑制与牙周炎相关的肺泡骨吸收。项目叙述：牙周炎是一种牙齿疾病，口腔细菌会导致炎症破坏牙齿。在此应用中，我们将研究抑制破骨细胞的机制，即破坏牙周炎中牙骨的细胞。我们预计我们的研究将产生可用于治疗干预措施以抑制与牙周炎相关的骨骼和牙齿破坏的见解。