Negative Regulation of Osteoclastogenesis

破骨细胞生成的负调控

• 批准号: 9089604
• 负责人: Lionel B Ivashkiv
• 金额: $ 43.88万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089604
• 关键词: Acute; BCL6 gene; Binding; Bone Resorption; Bone remodeling; Cell Lineage; Cells; Coupled; Coupling; Disease; Equilibrium; Feedback; Formulation; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; ITAM; Immunology; Implant; Infection; Inflammation; Inflammatory; Interferon Type II; Knowledge; Laboratories; Ligands; Macrophage Colony-Stimulating Factor; Mediating; Molecular; Musculoskeletal; Myelogenous; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Pathway interactions; Periodontitis; Phase; Physiological; Proteins; Regulation; 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 erosion; bone loss; bone mass; cytokine; gamma secretase; inflammatory bone loss; microbial; novel; novel strategies; novel therapeutic intervention; osteoclastogenesis; pathologic bone resorption; receptor

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-γ 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）：髓系破骨细胞是唯一有效的骨吸收细胞。破骨细胞是维持肌肉骨骼完整性和调节骨量的生理骨重塑的吸收阶段所必需的。在生理条件下，破骨细胞的生成和功能受到严格调控，并与成骨细胞谱系的功能耦合。许多与过度骨吸收和骨质流失相关的病理状况的特征是正常调节/偶联的丧失和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发生的新机制，并利用这些信息开发新的治疗方法来抑制病理性骨吸收。炎症是病理性骨质流失的重要驱动因素。炎症通过抑制成骨细胞介导的骨形成来减少骨量，同时通过增加破骨细胞的分化和骨吸收功能来强烈促进骨吸收。因此，炎症在诸如类风湿关节炎、牙周炎、感染和骨科植入物松动等疾病的炎症部位诱导局部骨侵蚀/骨溶解。最近的工作，包括我们实验室的贡献，已经清楚地表明，有效的炎症因子，如炎症细胞因子IFN-γ和GM-CSF以及toll样受体（TLRs）的配体，感知微生物产物和组织损伤，也诱导抑制破骨细胞生成的反馈抑制机制，从而限制炎症环境下发生的骨吸收量。关于炎症因子诱导的反馈抑制机制限制破骨细胞的发生尚不清楚。基于我们的总体假设，即增强反馈机制是抑制病理性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抑制破骨细胞发生的机制。我们发现了两种新的互补机制，炎症因子，包括Toll样受体和itam相关受体的配体，抑制破骨细胞前体的分化。它们是：1；调节蛋白水解途径，产生M-CSF的Fms受体的生物活性细胞内片段。2. 诱导BCL6转录抑制因子抑制破骨细胞生成“主调控因子”NFATc1的表达。这些新的抑制机制针对破骨细胞分化所需的两种主要非冗余蛋白Fms和NFATc1，并有效抑制破骨细胞的发生。我们将描述这些抑制机制，以获得知识，可用于开发新的方法来抑制破骨细胞发生和病理性骨吸收，通过增加这些机制的治疗。