Negative Regulation of Human Osteoclastogenesis

人类破骨细胞生成的负调控

• 批准号: 7555286
• 负责人: Lionel B Ivashkiv
• 金额: $ 43.75万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 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/7555286
• 关键词: 3' Untranslated Regions; Automobile Driving; Bacteria; Bone Resorption; Bone remodeling; Cell Lineage; Cell Wall; Cells; Chromatin; Chronic; Defect; Dental Plaque; Development; Disease; Disease Progression; Epigenetic Process; Equilibrium; Feedback; Generations; Genetic Transcription; Healed; Human; Immune; Inflammation; Inflammatory; Interleukin-10; Invaded; Lipopolysaccharides; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Modification; 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; Rate; 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; cytokine; healing; inflammatory bone resorption; insight; microbial; novel therapeutics; oral bacteria; oral biofilm; osteoclastogenesis; pathogenic bacteria; receptor; response; soft tissue; species difference

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）：牙周炎是一种慢性感染/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失调和破坏。该应用将重点关注炎症性骨吸收过程中破骨细胞生成的抑制机制。针对致病性口腔细菌的细胞激活和炎症介质产生是由识别保守微生物分子的“模式识别受体”介导的。最重要的模式识别受体包括 Toll 样受体 2 (TLR2) 和 TLR4，它们与牙周炎中炎症性骨吸收的驱动有关。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。牙周炎中炎症的程度和相关骨丢失的速度取决于炎症因子之间的平衡以及对抗炎症和骨吸收并促进愈合的反馈和稳态机制的相对效力。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，与炎症的生理消退期间或疾病静止期期间发生的有效稳态调节相反。我们的首要假设是，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，我们启动了研究，以了解在牙周病等炎症环境中抑制破骨细胞形成的分子机制。我们发现 IL-10 是一种由 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（对破骨细胞生成至关重要的关键受体）信号传导来抑制破骨细胞生成。此外，我们发现TLRs通过抑制破骨细胞前体发育过程中的RANK和TREM-2表达，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类和小鼠破骨细胞生成调节之间的定性和定量差异，包括 TREM-2 的差异调节，这可能有助于解释骨重塑调节的物种差异。在此应用中，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。我们预计我们的研究将深入了解体内平衡调节，可用于抑制与牙周炎相关的牙槽骨吸收的治疗干预。项目叙述：牙周炎是一种牙科疾病，口腔细菌引起炎症，破坏牙齿。在此应用中，我们将研究抑制破骨细胞的机制，破骨细胞是牙周炎中破坏牙骨的细胞。我们预计我们的研究将产生可用于治疗干预的见解，以抑制与牙周炎相关的骨骼和牙齿破坏。