Negative Regulation of Osteoclastogenesis by Inflammatory Signals

炎症信号对破骨细胞生成的负调控

• 批准号: 8838046
• 负责人: Kyung-Hyun Park-Min
• 金额: $ 24.9万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838046
• 关键词: Address; Affect; Animal Model; Automobile Driving; Blocking Antibodies; Bone Resorption; Cell Lineage; Cell Nucleus; Cells; Chronic; Cleaved cell; Clinical; Clinical Trials; Cytolysis; Data; Development; Disease; Disease Progression; Feedback; Fibroblasts; Generations; Goals; Human; Immune; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Joints; Ligands; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Molecular; Morbidity - disease rate; Mus; Myelogenous; Osteoclasts; Pathogenesis; Phase; Physiological; Process; Proteolytic Processing; Reaction; Receptor Protein-Tyrosine Kinases; Regulation; Resolution; Rheumatoid Arthritis; Role; Series; Signal Pathway; Signal Transduction; Synovial Cell; System; TNF gene; TNF-alpha converting enzyme; TRANCE protein; Testing; Therapeutic Intervention; Time; Tissues; Toll-like receptors; base; bone; bone erosion; c-fms Proto-Oncogenes; cytokine; in vivo; inflammatory bone resorption; insight; joint destruction; macrophage; novel strategies; novel therapeutic intervention; osteoclastogenesis; overexpression; prevent; progenitor; receptor

Negative Regulation of Osteoclastogenesis by Inflammatory signals Rheumatoid arthritis (RA) is a chronic inflammatory disease in which immune cells and synovial fibroblasts produce pro-inflammatory cytokines, in particular TNF and IL-1, and drive an inflammatory state leading to destruction of affected joints. One important consequence of inflammation is the generation of osteoclasts, myeloid lineage cells that effectively resorb bone and thus are directly responsible for bone erosion and morbidity in RA. This application will focus on mechanisms of inhibition of the generation of osteoclasts. TLRs (Toll-like Receptors) are potent activators of inflammation and have been implicated in driving inflammatory bone resorption. However, at the same time that they activate inflammation, TLRs also induce potent homeostatic mechanisms to limit the intensity of inflammation and thus limit associated tissue damage. Disease progression is evidence of relatively ineffective feedback inhibition that is unable to restrain inflammation and bone resorption. Thus, we have initiated studies to understand the effective homeostatic regulation that occurs during physiological resolution of inflammation and quiescent phases of disease. Our overall hypothesis is that augmentation of physiological homeostatic mechanisms represents an effective approach to limiting bone resorption associated with inflammation and thus can form the basis for novel therapeutic approaches. We have found that TLR stimulation strongly suppresses osteoclastogenesis by inhibiting RANK, a key receptor required for osteoclastogenesis. The mechanism of TLR-mediated inhibition involves induction of a M-CSF receptor (c-Fms) shedding and proteolytic processing by activated TNF-alpha converting enzyme (TACE, also known as ADAM-17), potentially leading to cellular unresponsiveness to M-CSF. Cleaved c-Fms subsequently undergoes a series of proteolytic reactions that results in generation of the 50-kDa intracellular domain cleavage fragments (referred to as MICD). Interestingly, our results reveal that MICD is able to translocate into the nucleus, and expression of MICD enhances osteoclastogenesis. MICD generation is also diminished by inflammatory signals. We will use human systems that are directly relevant for RA pathogenesis as well as mouse system to test the in vivo role of MICD and TACE in inflammatory diseases. The long-term goals of this project are to: 1) understand molecular mechanisms by which c-Fms shedding and processing into MICD regulate osteoclastogenesis and the association of TACE with this process, and 2) identify the role of MICD in M-CSF signaling and differentiation of osteoclasts and macrophages. We anticipate that our studies will yield insights into homeostatic regulation that can not only be exploited for therapeutic interventions to suppress bone resorption associated with joint destruction but will also broaden understanding of the actions of M-CSF in the field of osteoimmunology.

炎症信号对破骨细胞生成的负调控 类风湿性关节炎（RA）是一种慢性炎症性疾病， 成纤维细胞产生促炎细胞因子，特别是TNF和IL-1，并驱动炎症状态 导致受影响关节的破坏。炎症的一个重要后果是产生 破骨细胞，有效吸收骨的髓系细胞，因此直接负责骨 侵蚀和发病率。本申请将集中在抑制产生的机制， 破骨细胞TLR（Toll样受体）是炎症的有效激活剂，并且已经牵涉到炎症反应。 导致炎症性骨吸收然而，在激活炎症的同时，TLR也 诱导有效的体内平衡机制，以限制炎症的强度，从而限制相关组织 损害疾病进展是相对无效的反馈抑制的证据， 抑制炎症和骨吸收。因此，我们已经开始研究，以了解有效的 在炎症的生理消退和炎症的静止期期间发生的稳态调节， 疾病我们的总体假设是，生理稳态机制的增强代表了 一种有效的方法来限制与炎症相关的骨吸收，因此可以形成基础， 新的治疗方法。 我们已经发现TLR刺激通过抑制RANK，一种抑制破骨细胞生成的蛋白， 破骨细胞生成所需的关键受体。TLR介导的抑制机制涉及诱导 M-CSF受体（c-Fms）通过活化TNF-α转化而脱落和蛋白水解加工 酶（TACE，也称为ADAM-17），可能导致细胞对M-CSF无反应。 切割的c-Fms随后经历一系列蛋白水解反应，导致产生蛋白水解酶。 50-kDa胞内结构域切割片段（称为MICD）。有趣的是，我们的结果显示， MICD能够移位到细胞核中，并且MICD的表达增强破骨细胞生成。MICD 炎症信号也减少了生成。我们将使用人类系统， 用于RA发病机制以及小鼠系统，以测试MICD和TACE在炎症中的体内作用。 疾病该项目的长期目标是：1）了解c-Fms的分子机制， 脱落和加工成MICD调节破骨细胞生成，TACE与此相关 过程，和2）确定MICD在M-CSF信号传导和破骨细胞分化中的作用， 巨噬细胞我们预计，我们的研究将产生对稳态调节的见解，不仅可以 用于治疗干预以抑制与关节破坏相关的骨吸收， 也将扩大对M-CSF在骨免疫学领域的作用的理解。