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理尚不清楚，但是几个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，巨噬细胞，中性粒细胞和骨化剂（OC）[1-3]。确定影响骨免疫系统的常见信号分子及其对正常和病理骨质流失的影响可能为多种疾病（例如类风湿关节炎）的未来疗法奠定基础。我们发现PLC32是这样的候选人。除了B细胞有缺陷外，PLC32 - / - 小鼠由于异常破骨细胞的募集和功能而是骨质原膜性[4] [5]。 PLC32在破骨细胞发生过程中影响了两种主要的RANKL诱导的信号通路，即NF：B和NFAT激活，以及在吸收细胞中1V23整合素粘合剂结构的激活和适当定位。出乎意料的是，我们还发现，PLC32 - / - 小鼠受到与两种不同的关节炎模型相关的炎症的叛乱，严格依赖于嗜中性粒细胞的血清诱发关节炎以及抗原诱导的关节炎，与T细胞激活相关。尽管PLC32在T细胞中未表达，但PLC32控制树突状细胞（DC）激活T细胞的能力。抗原脉冲PLC32 - / - DC，但不是WT DC，在局部膝关节注射抗原后，将炎症反应注射到WT小鼠中时，无法引发炎症反应。相反，将抗原脉冲WT DC注射到PLC32 - / - 小鼠中完全恢复了炎症反应，而无需引起破骨细胞募集和局灶性骨溶解。这些有趣的数据位置PLC32是炎症性关节炎期间骨完整性和免疫反应的关键调节剂。基于这一观察结果，我们假设PLC32在炎症性关节炎期间DC介导的T细胞激活需要PLC32。因此，我们旨在研究Plc32在抗原表现和在炎症性关节炎过程中的DC运动中的作用。我们认为，将原始提案的重点从了解PLC32在OC中研究其在DC中的作用的作用的重点可能导致旨在针对类风湿关节炎的炎症和骨化成分的新治疗途径。该申请是为了回应通知NOT-OD-09-058：NIH宣布恢复法案的可用性用于竞争性修订。 公共卫生相关性：该提案的总体目标是扩大我们原始R01提案的目标，从研究PLC32介导的破骨细胞分化和功能的调节，以检查PLC32在DC介导的T细胞激活中的作用。具体而言，我们旨在研究plc32在抗原呈递中的作用以及在炎症性关节炎期间T细胞激活所需的两个关键事件中DC在淋巴结中募集的作用。由于免疫细胞与破骨细胞之间的相互作用越来越多，因此确定影响骨可能免疫系统的常见信号分子及其对正常和病理骨质流失的影响可能为未来疾病（如炎性关节炎）的疾病提供基础。 。