Cytokine Regulation of RA Synoviocyte Phenotype
RA滑膜细胞表型的细胞因子调节
基本信息
- 批准号:8423784
- 负责人:
- 金额:$ 36.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcuteAntigen-Antibody ComplexArthritisBone ResorptionCell LineageCellsComplexDiseaseEnvironmentEquilibriumFamily memberFc ReceptorFibrinFibrinogenFibroblastsGoalsHumanITAMImmuneInflammationInflammatoryIntegrinsInterferonsInterleukin-1Interleukin-10JointsLeadMediatingMolecularMorbidity - disease rateMusMyelogenousNatureOsteoclastsOsteolysisOsteoporosisPathogenesisPathway interactionsPharmacia brand of estropipatePhenotypePlayProductionReceptor SignalingRegulationRheumatoid ArthritisRoleSamplingSignal PathwaySignal TransductionSynovial CellSynovial MembraneSynovitisSystemTNF geneTNFSF11 geneTestingTherapeuticTissuesbonecytokineinflammatory bone resorptioninsightjoint injurymacrophageosteoclastogenesispathologic bone resorptionreceptorreceptor couplingreceptor functionresearch studyresponse
项目摘要
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 ¿2 integrins and immune complexes ligate Fc receptors. This finding was surprising, as ¿2
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.
类风湿性关节炎(RA)中的滑膜细胞受到复杂的炎症环境的调节。长
本项目的长期目标是了解RA滑膜因子的信号如何整合,
确定滑膜髓系细胞(包括巨噬细胞)的表型和功能,
破骨细胞巨噬细胞通过产生细胞因子,
炎症和破骨细胞介导病理性骨吸收。
破骨细胞分化依赖于TNF家族成员RANKL。在关节发炎期间,
炎性因子如TNF和IL-1增加破骨细胞分化,导致骨增加
骨吸收是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,
在滑膜炎症过程中抑制破骨细胞生成,
明白我们的总体假设是,增强抑制骨骼的稳态机制,
骨吸收代表了减少与RA相关的关节损伤的有效治疗方法。
因此,我们已经着手确定哪些因素存在于滑膜炎能够抑制
破骨细胞生成,并确定其作用机制。
我们已经发现,纤维蛋白(原)和免疫复合物,两个因子在RA中高水平表达,
滑膜并参与炎症发病机制,抑制破骨细胞生成。纤维蛋白原激活
通过整合素和免疫复合物连接Fc受体的信号传导。这一发现令人惊讶,因为
整合素和Fc受体通过基于免疫受体酪氨酸激活基序(ITAM)介导的信号传导
先前已经涉及通过提供促进破骨细胞分化的途径
有效RANK反应所需的共刺激信号。此外,我们还发现ITAM-
RA巨噬细胞介导的抑制性信号传导是有缺陷的,这表明疾病相关的改变
在ITAM信号转导损害正常情况下抑制破骨细胞生成的稳态机制中,
非病理性炎症我们的研究结果使我们假设ITAM可以同时提供
破骨细胞生成的正信号和负信号,
治疗上可用于抑制RA中的炎性骨吸收。
在本申请中,我们将研究纤维蛋白原和
免疫复合物抑制破骨细胞生成。我们将主要使用人类系统,
与RA发病机制有关。我们还将用RA样品进行翻译实验。我们
预计我们的研究将提供可用于调节激活和激活平衡的见解,
治疗性抑制ITAM介导的信号传导以抑制RA中的炎性骨质溶解。
项目成果
期刊论文数量(0)
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Lionel B Ivashkiv其他文献
Lionel B Ivashkiv的其他文献
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{{ truncateString('Lionel B Ivashkiv', 18)}}的其他基金
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- 资助金额:
$ 36.01万 - 项目类别:
Grant-in-Aid for international Scientific Research