Anti-osteogenic functions of lipocalin2, an innate immune protein, during autoimmune arthritis

脂质运载蛋白2（一种先天免疫蛋白）在自身免疫性关节炎过程中的抗成骨功能

• 批准号: 9385901
• 负责人: Shashidharamurthy Taval
• 金额: $ 8.4万
• 依托单位: PHILADELPHIA COLLEGE OF OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385901
• 关键词: Acute-Phase Proteins; Adult; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthritis; Attenuated; Autoimmune Diseases; Autoimmune Process; Automobile Driving; B-Lymphocytes; Biochemical Markers; Biological; Bone Marrow Cells; Bone Resorption; Bone Tissue; Bone remodeling; C-terminal; Cells; Chronic; Collagen; Data; Development; Disease; Dissection; Exhibits; Future; Goals; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-10; Interleukin-6; Joints; Knock-out; Knockout Mice; LCN2 gene; Lead; Mediating; Metacarpal bone; Methods; Modeling; Mus; NF-kappa B; Orthologous Gene; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Play; Prevention; Proteins; Publishing; Reaction; Recombinants; Refractory; Reporting; Resolution; Rheumatoid Arthritis; Role; Serum; Severities; Skeleton; Synovial Cell; Synovial Fluid; Synovial joint; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Validation; Wild Type Mouse; X-Ray Computed Tomography; autoimmune arthritis; autoinflammatory; base; bone; bone erosion; bone loss; bone turnover; cytokine; design; disability; histological stains; humanized mouse; immunoregulation; improved; indexing; inhibitor/antagonist; insight; joint destruction; joint injury; macrophage; mouse model; novel; novel therapeutics; osteoclastogenesis; osteogenic; prevent; targeted treatment; therapeutic target

PROJECT SUMMARY: Rheumatoid arthritis (RA) is a collective term for chronic idiopathic autoimmune inflammatory diseases of synovial joints, which affect an estimated 43 million adults in the US and is a leading cause for disability. RA is associated with elevated levels of a numerous acute phase proteins (APPs), including lipocalin 2 (Lcn2), that drive/dampen the inflammatory response. However, the biological activity, and thus therapeutic potential, of some of the most dynamically regulated APPs remain unexplored. The upregulation of APP such as lipocalin2 (Lcn2) during various inflammatory disorders including RA could be result of inflammatory reactions, but recent studies have shown that upregulated Lcn2 has multifunctional biological activity including bone remodeling function, apart from serving as a disease correlative marker. These studies suggest that it may play a central role during the pathogenesis of RA. More recently, we observed that Lcn2 knockout mice exhibited exacerbated arthritis with severe metacarpal and articular bone damage with elevated levels of pro-inflammatory cytokines (IL-1β and IL-6) when compared to its wild type littermates in serum-transfer arthritis model. In addition, Lcn2 knockout alternative macrophages (M2) exhibited reduced secretion of anti-inflammatory cytokines such as TGF-β1 and IL-10, but upregulation of pro-inflammatory cytokines (TNF-α and IL-1β) by classical macrophages (M1). Taken together, upregulation of Lcn2 during RA may play a crucial role in limiting inflammation and prevent severe bone erosion at the arthritic microenvironment. Therefore, we hypothesize that during arthritis systemically/locally upregulated Lcn2 attenuates the severity of the bone damage by limiting the inflammation and bone erosion. Lcn2 consequently plays an indispensable role in prevention of serious bone damage during autoimmune arthritis. Thus, the goal of this proposal is to investigate the function and mechanism of action of Lcn2 during bone remodeling in IC-mediated autoimmune arthritis. Therefore, establishing the functional role of this dynamically regulated protein will improve our understanding of the pathogenesis of the disease and lead to development of novel therapeutic strategies to treat RA.

项目概要： 风湿性关节炎（RA）是慢性特发性自身免疫性炎性疾病的统称， 滑膜关节，这影响了美国估计4300万成年人，是残疾的主要原因。RA是 与包括脂质运载蛋白2（Lcn 2）在内的许多急性期蛋白（APP）水平升高相关， 驱动/抑制炎症反应。然而，生物活性，从而治疗潜力， 一些最受动态监管的APP仍未被探索。APP如脂质运载蛋白2的上调 在包括RA在内的各种炎症性疾病期间，Lcn 2可能是炎症反应的结果，但最近 研究表明，上调的Lcn 2具有多功能生物活性， 功能，除了作为疾病相关标志物。这些研究表明，它可能发挥了核心作用， 在RA发病过程中的作用。 最近，我们观察到Lcn 2基因敲除小鼠表现出严重的关节炎， 掌骨和关节骨损伤伴促炎细胞因子（IL-1β和IL-6）水平升高 在血清转移关节炎模型中与其野生型同窝仔相比。此外，Lcn 2敲除 替代性巨噬细胞（M2）表现出抗炎细胞因子（如TGF-β1和 IL-10，但经典巨噬细胞（M1）上调促炎细胞因子（TNF-α和IL-1β）。 综上所述，类风湿关节炎期间Lcn 2的上调可能在限制炎症和预防关节炎中起着至关重要的作用。 关节炎微环境中严重的骨质侵蚀。因此，我们假设在关节炎期间 全身/局部上调的Lcn 2通过限制炎症减轻骨损伤的严重性 和骨质侵蚀因此，LCN 2在预防严重骨损伤中起着不可或缺的作用， 自身免疫性关节炎因此，本提案的目标是研究 IC介导的自身免疫性关节炎骨重建过程中的Lcn 2因此，确定 这种动态调节的蛋白质将提高我们对疾病发病机制的理解， 开发治疗RA的新治疗策略。