Negative Regulation of Osteoclastogenesis

破骨细胞生成的负调控

基本信息

批准号：
8481532
负责人：
Lionel B Ivashkiv
金额：
$ 42.12万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481532
关键词：
Acute BCL6 gene Binding Bone Resorption Bone remodeling Cell Lineage Cells Coupled Coupling Disease Drug Formulations Equilibrium Feedback Generations Goals Granulocyte-Macrophage Colony-Stimulating Factor ITAM Immunology Implant Infection Inflammation Inflammatory Interferon Type II Interferons Knowledge Laboratories Ligands Macrophage Colony-Stimulating Factor Mediating Molecular Musculoskeletal Myelogenous Orthopedics Osteoblasts Osteoclasts Osteogenesis Osteolysis Pathway interactions Periodontitis Phase Physiological Proteins Regulation Relative (related person)Rheumatoid Arthritis Signal Transduction Site TNFSF11 gene Therapeutic Tissues Toll-like receptors Toxic effect Transcription Repressor/Corepressor Tumor necrosis factor receptor 11b Work base bone bone loss bone mass cytokine microbial novel novel strategies novel therapeutic intervention osteoclastogenesis pathologic bone resorption receptor secretase

项目摘要

DESCRIPTION (provided by applicant): Myeloid lineage osteoclasts are the sole effective bone-resorbing cells. Osteoclasts are required for the resorptive phase of physiological bone remodeling that maintains musculoskeletal integrity and regulates bone mass. Under physiological conditions the generation and function of osteoclasts is tightly regulated and coupled to the function of bone-forming osteoblast lineage cells. Many pathological conditions associated with excessive bone resorption and bone loss are characterized by loss of normal regulation/coupling, and excessive osteoclastogenesis. The long term goals of this project are to elucidate new mechanisms that suppress osteoclastogenesis, with the associated goal of using this information to develop new therapeutic approaches to suppress pathological bone resorption. Inflammation is an important driver of pathological bone loss. Inflammation decreases bone mass by suppressing osteoblast-mediated bone formation, and concomitantly strongly promoting bone resorption by increasing the differentiation and bone-resorbing function of osteoclasts. Thus, inflammation induces local bone erosion/osteolysis at inflammatory sites in diseases such as rheumatoid arthritis, periodontitis, infections, and orthopedic implant loosening. Recent work, including contributions from our laboratory, has made clear that potent inflammatory factors, such as the inflammatory cytokines IFN-? and GM-CSF and ligands for Toll-like receptors (TLRs) that sense microbial products and tissue damage, also induce feedback inhibition mechanisms that restrain osteoclastogenesis and thus limit the amount of bone resorption that occurs in inflammatory settings. Little is known about feedback inhibitory mechanisms induced by inflammatory factors to limit osteoclastogenesis. Based on our overarching hypothesis that augmenting feedback mechanisms represents an attractive alternative therapeutic approach to suppress pathologic bone resorption, we have investigated mechanisms by which inflammatory signaling restrains osteoclastogenesis. We have discovered two novel and complementary mechanisms by which inflammatory factors, including ligands for Toll like receptors and ITAM-associated receptors, suppress differentiation of osteoclast precursors. These are: 1. Modulation of a proteolytic pathway that generates a biologically active intracellular fragment of the Fms receptor for M-CSF. 2. Induction of the BCL6 transcriptional repressor to inhibit expression of the 'master regulator' of osteoclastogenesis NFATc1. These novel inhibitory mechanisms target two major nonredundant proteins required for osteoclast differentiation, Fms and NFATc1, and effectively inhibit osteoclastogenesis. We will characterize these inhibitory mechanisms to obtain knowledge that can be used to develop new approaches to suppress osteoclastogenesis and pathologic bone resorption by augmenting these mechanisms therapeutically.

描述（由申请人提供）：髓样谱系破骨细胞是唯一有效的骨呈现细胞。破骨细胞是维持肌肉骨骼完整性并调节骨骼质量的生理骨重塑的吸收阶段所必需的。在生理条件下，破骨细胞的产生和功能受到严格调节，并与成骨成骨细胞谱系细胞的功能结合在一起。与过度骨吸收和骨质流失相关的许多病理状况的特征是正常调节/耦合以及过度的破骨细胞生成。该项目的长期目标是阐明抑制破骨细胞生成的新机制，其相关目标是使用此信息来开发新的治疗方法来抑制病理骨吸收。炎症是病理骨质流失的重要驱动力。炎症通过抑制成骨细胞介导的骨骼形成来减少骨骼，并通过增加破骨细胞的分化和骨变差功能，从而强烈促进骨吸收。因此，炎症会诱导诸如类风湿关节炎，牙周炎，感染和骨科植入物松动等疾病的炎症部位的局部骨侵蚀/骨溶解。最近的工作，包括我们实验室的贡献，已经明确表明，有效的炎症因素，例如炎症性细胞因子IFN-？感知微生物产物和组织损伤的TOLL样受体（TLR）的GM-CSF和配体，还诱导抑制破骨质发生的反馈抑制机制，从而限制炎症环境中发生的骨吸收量。关于炎症因子诱导的反馈抑制机制几乎了解，以限制破骨构成的发生。基于我们的总体假设，即增强反馈机制是抑制病理骨吸收的一种有吸引力的替代治疗方法，我们研究了炎症信号传导限制破骨细胞发生的机制。我们发现了两种新型和互补的机制，通过这些机制，包括受体和ITAM相关受体的炎性因子，包括抑制破骨细胞前体的分化。这些是：1。对M-CSF的FMS受体的生物活性细胞内片段的调节。 2。诱导Bcl6转录阻遏物抑制骨质质发生的“主要调节剂” NFATC1的表达。这些新型的抑制性机制靶向破骨细胞分化，FMS和NFATC1所需的两种主要非冗余蛋白质，并有效抑制破骨细胞生成。我们将表征这些抑制性机制，以获取可用于开发新方法来抑制破骨细胞生成和病理骨吸收的知识，通过治疗这些机制来抑制破骨细胞生成和病理骨吸收。