REGULATORY PATHWAYS IN OSTEOCLAST FORMATION AND FUNCTION

破骨细胞形成和功能的调节途径

• 批准号: 7810845
• 负责人: Roberta Faccio
• 金额: $ 17.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2010-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810845
• 关键词: Adhesives; Adult; Affect; Antigen Presentation; Antigens; Arthritis; B-Cell Development; B-Lymphocytes; Cells; Child; Data; Dendritic Cells; Development; Disease; Event; Funding; Future; Goals; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Integrins; Knee; Lead; Mediating; Modeling; Mus; Osteoclasts; Osteolysis; Osteolytic; Pathogenesis; Physiologic pulse; Positioning Attribute; Reaction; Recovery; Regulation; Regulatory Pathway; Rheumatoid Arthritis; Role; Serum; Signal Pathway; Signaling Molecule; Structure; Synovial Cell; T-Cell Activation; T-Lymphocyte; United States National Institutes of Health; abstracting; autoimmune arthritis; base; bone; bone loss; cell motility; lymph nodes; macrophage; neutrophil; novel therapeutics; osteoclastogenesis; public health relevance; response

DESCRIPTION (provided by applicant): Project Summary/Abstract The exact pathogenesis of arthritis in children or adults is not known, but several cells contribute to the development of autoimmune arthritis including T and B lymphocytes, synovial cells, macrophages, neutrophils and osteoclasts (OC) [1-3]. Identifying common signaling molecules affecting the osteo-immune system and their impact on normal and pathological bone loss may lay the groundwork for future therapies for the variety of diseases such as rheumatoid arthritis. We have found PLC32 to be such candidate. In addition to defective B cell development, PLC32-/- mice are osteopetrotic due to aberrant osteoclast recruitment and function [4] [5]. PLC32 affects the two major RANKL-induced signaling pathways during osteoclastogenesis, namely NF:B and NFAT activation, as well as activation and proper localization of 1v23 integrin adhesive structure in the resorbing cell. Unexpectedly, we also found that PLC32 -/- mice are protected from the insurgence of inflammation associated with two different models of arthritis, the serum induced arthritis which is strictly dependent on neutrophils [6], and the antigen induced arthritis which relays on T cell activation. Although PLC32 is not expressed in T cells, PLC32 controls the ability of dendritic cells (DC) to activate T cells. Antigen pulsed PLC32-/- DC, but not WT DC, fail to initiate an inflammatory reaction when injected into WT mice following a local knee injection of the antigen. Conversely, injection of antigen pulsed WT DC into PLC32-/- mice completely restores the inflammatory response without eliciting osteoclast recruitment and focal osteolysis. These intriguing data position PLC32 as a critical modulator of bone integrity and immune responses during inflammatory arthritis. Based on this observation, we hypothesize that PLC32 is required for DC-mediated T cell activation during inflammatory arthritis. Thus, we aim to study the role of PLC32 in antigen presentation and in DC motility during inflammatory arthritis. We believe that expanding the focus of our original proposal from understanding the role of PLC32 in the OCs to study its effects in DC, may lead to new therapeutic avenues aimed at targeting the inflammatory and osteolytic components of rheumatoid arthritis. This application is in response to Notice NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to expand the goals of our original R01 proposal from studying PLC32- mediated regulation of osteoclast differentiation and function to examining the role of PLC32 in DC-mediated T cell activation. Specifically, we aim to investigate the role of PLC32 in antigen presentation and in the recruitment of DCs to the lymph nodes, both critical events required for T cell activation, during inflammatory arthritis. Since the interaction between immune cells and osteoclast is increasingly recognized, identifying common signaling molecules affecting the osteo-immune system and their impact on normal and pathological bone loss may lay the groundwork for future therapies for the variety of diseases such as inflammatory arthritis. .

描述（由申请人提供）：项目摘要/摘要儿童或成人关节炎的确切发病机制尚不清楚，但多种细胞有助于自身免疫性关节炎的发展，包括 T 和 B 淋巴细胞、滑膜细胞、巨噬细胞、中性粒细胞和破骨细胞 (OC) [1-3]。识别影响骨免疫系统的常见信号分子及其对正常和病理性骨质流失的影响可能为未来治疗类风湿性关节炎等各种疾病奠定基础。我们发现 PLC32 就是这样的候选者。除了 B 细胞发育缺陷外，PLC32-/- 小鼠还因破骨细胞募集和功能异常而出现骨石症 [4] [5]。 PLC32 影响破骨细胞生成过程中 RANKL 诱导的两个主要信号通路，即 NF:B 和 NFAT 激活，以及再吸收细胞中 1v23 整合素粘附结构的激活和正确定位。出乎意料的是，我们还发现 PLC32 -/- 小鼠免受与两种不同关节炎模型相关的炎症的影响，即严格依赖于中性粒细胞的血清诱导的关节炎[6]，以及依赖于 T 细胞激活的抗原诱导的关节炎。尽管 PLC32 不在 T 细胞中表达，但 PLC32 控制树突状细胞 (DC) 激活 T 细胞的能力。抗原脉冲的 PLC32-/- DC（而非 WT DC）在局部膝盖注射抗原后注射到 WT 小鼠中时未能引发炎症反应。相反，将抗原脉冲的WT DC注射到PLC32-/-小鼠中可以完全恢复炎症反应，而不会引起破骨细胞募集和局灶性骨溶解。这些有趣的数据将 PLC32 定位为炎症性关节炎期间骨完整性和免疫反应的关键调节剂。基于这一观察，我们假设 PLC32 是炎症性关节炎期间 DC 介导的 T 细胞激活所必需的。因此，我们的目的是研究 PLC32 在炎症性关节炎期间抗原呈递和 DC 运动中的作用。我们相信，将我们最初提案的重点从了解 PLC32 在 OC 中的作用扩展到研究其在 DC 中的作用，可能会带来针对类风湿性关节炎的炎症和溶骨成分的新治疗途径。本申请是对通知 NOT-OD-09-058 的回应：NIH 宣布恢复法案资金可用于竞争性修订。 公共健康相关性：该提案的总体目标是将我们最初的 R01 提案的目标从研究 PLC32 介导的破骨细胞分化和功能调节扩展到检查 PLC32 在 DC 介导的 T 细胞激活中的作用。具体来说，我们的目的是研究 PLC32 在抗原呈递和 DC 募集到淋巴结中的作用，这两个过程都是炎症性关节炎期间 T 细胞激活所需的关键事件。由于免疫细胞和破骨细胞之间的相互作用日益得到认可，识别影响骨免疫系统的常见信号分子及其对正常和病理性骨质流失的影响可能为未来治疗炎症性关节炎等各种疾病奠定基础。 。