Cytokine Regulation of RA Synoviocyte Phenotype

RA滑膜细胞表型的细胞因子调节

• 批准号: 8042559
• 负责人: Lionel B Ivashkiv
• 金额: $ 37.91万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042559
• 关键词: Acute; Antigen-Antibody Complex; Arthritis; Bone Resorption; Cell Lineage; Cells; Complex; Disease; Environment; Equilibrium; Family member; Fc Receptor; Fibrin; Fibrinogen; Fibroblasts; Goals; Human; ITAM; Immune; Inflammation; Inflammatory; Integrins; Interferons; Interleukin-1; Interleukin-10; Joints; Lead; Mediating; Molecular; Morbidity - disease rate; Mus; Myelogenous; Nature; Osteoclasts; Osteolysis; Osteoporosis; Pathogenesis; Pathway interactions; Pharmacia brand of estropipate; Phenotype; Play; Production; Receptor Signaling; Regulation; Rheumatoid Arthritis; Role; Sampling; Signal Pathway; Signal Transduction; Synovial Cell; Synovial Membrane; Synovitis; System; TNF gene; TNFSF11 gene; Testing; Therapeutic; Tissues; bone; cytokine; inflammatory bone resorption; insight; joint injury; macrophage; osteoclastogenesis; pathologic bone resorption; public health relevance; receptor; receptor coupling; receptor function; research study; response

DESCRIPTION (provided by applicant): Synovial cells in rheumatoid arthritis (RA) are regulated by a complex inflammatory environment. The long term goals of this project are to understand how signals from RA synovial factors are integrated to determine the phenotype and function of synovial myeloid lineage cells, including macrophages and osteoclasts. Macrophages play a key role in RA pathogenesis by production of cytokines that drive inflammation, and osteoclasts mediate pathologic bone resorption. Osteoclast differentiation is dependent on the TNF family member RANKL. During joint inflammation, inflammatory factors such as TNF and IL-1 increase osteoclast differentiation leading to increased bone resorption that is a major contributor to morbidity in RA. The inflammatory synovial environment also activates homeostatic mechanisms to limit joint damage associated with inflammation. However, the factors that restrain osteoclastogenesis during synovial inflammation and their mechanisms of action are poorly understood. Our overarching hypothesis is that augmenting homeostatic mechanisms that suppress bone resorption represents an effective therapeutic approach to decrease joint damage associated with RA. Therefore, we have set out to determine which factors present during synovitis are capable of suppressing osteoclastogenesis, and to determine their mechanisms of action. We have found that fibrin(ogen) and immune complexes, two factors expressed at high levels in RA synovium and implicated in inflammatory pathogenesis, suppress osteoclastogenesis. Fibrinogen activates signaling via 22 integrins and immune complexes ligate Fc receptors. This finding was surprising, as 22 integrins and Fc receptors signal via immunoreceptor tyrosine-based activation motif (ITAM)-mediated pathways that have previously been implicated in promoting osteoclast differentiation by providing costimulatory signals required for effective RANK responses. In addition, we have found that ITAM- mediated inhibitory signaling was defective in RA macrophages, suggesting that disease-related alterations in ITAM signaling compromise homeostatic mechanisms that normally restrain osteoclastogenesis in acute nonpathological inflammatory settings. Our findings lead us to hypothesize that ITAMs can deliver both positive and negative signals for osteoclastogenesis, and that manipulation of the balance of these signals therapeutically can be used to suppress inflammatory bone resorption in RA. In this application, we will investigate molecular mechanisms and pathways by which fibrinogen and immune complexes inhibit osteoclastogenesis. We will predominantly use human systems that are directly relevant for RA pathogenesis. We will also perform translational experiments with RA samples. We anticipate that our studies will provide insights that can be utilized to modulate the balance of activating and suppressive ITAM-mediated signaling therapeutically to suppress inflammatory osteolysis in RA. PUBLIC HEALTH RELEVANCE: Osteoclasts play a key role in rheumatoid arthritis (RA) pathogenesis y mediating pathologic bone resorption. In this application we will investigate a new signaling pathway that inhibits osteoclast differentiation and is induced by fibrinogen and immune complexes, factors that are present in inflamed RA joint tissues. We anticipate that our studies will provide insights that can be utilized to increase inhibitory signaling therapeutically to suppress inflammatory bone destruction in RA.

描述（由申请人提供）：类风湿性关节炎（RA）的滑膜细胞受复杂的炎症环境调节。该项目的长期目标是了解RA滑膜因子的信号如何整合以确定滑膜髓系细胞（包括巨噬细胞和破骨细胞）的表型和功能。巨噬细胞通过产生驱动炎症的细胞因子和破骨细胞介导病理性骨吸收，在RA发病过程中发挥关键作用。破骨细胞分化依赖于TNF家族成员RANKL。在关节炎症期间，炎症因子如TNF和IL-1增加破骨细胞分化，导致骨吸收增加，这是RA发病率的主要原因。炎症性滑膜环境也激活体内平衡机制，以限制与炎症相关的关节损伤。然而，在滑膜炎症期间抑制破骨细胞生成的因素及其作用机制尚不清楚。我们的总体假设是，增强抑制骨吸收的稳态机制是减少关节炎相关关节损伤的有效治疗方法。因此，我们已经着手确定滑膜炎期间存在的哪些因素能够抑制破骨细胞生成，并确定其作用机制。我们发现纤维蛋白（原）和免疫复合物这两个因子在RA滑膜中高水平表达并参与炎症发病机制，抑制破骨细胞的发生。纤维蛋白原通过22个整合素和免疫复合物连接Fc受体激活信号。这一发现令人惊讶，因为22个整合素和Fc受体通过免疫受体酪氨酸激活基序（ITAM）介导的途径进行信号传递，这些途径先前被认为通过提供有效RANK反应所需的共刺激信号来促进破骨细胞分化。此外，我们发现ITAM介导的抑制信号在RA巨噬细胞中是有缺陷的，这表明ITAM信号的疾病相关改变破坏了在急性非病理性炎症环境中通常抑制破骨细胞生成的稳态机制。我们的研究结果使我们假设itam可以为破骨细胞的发生提供积极和消极的信号，并且在治疗上操纵这些信号的平衡可以用来抑制RA的炎症性骨吸收。在这个应用中，我们将研究纤维蛋白原和免疫复合物抑制破骨细胞发生的分子机制和途径。我们将主要使用与类风湿性关节炎发病机制直接相关的人体系统。我们还将对RA样品进行转化实验。我们预计我们的研究将提供可用于调节激活和抑制itam介导的信号传导平衡的见解，以治疗性地抑制RA的炎症性骨溶解。