Investigating the IL-4/13 Axis in Osteoarthritis

研究骨关节炎中的 IL-4/13 轴

• 批准号: 10553629
• 负责人: William H Robinson
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553629
• 关键词: Anti-Inflammatory Agents; Asthma; Award; Basophils; Biological Markers; Blood; Bone remodeling; Caring; Cartilage; Cells; Chondrocytes; Clinical; Clinical Trials; Cytoprotection; Degenerative polyarthritis; Development; Disease; Drug Targeting; Evaluation; Exhibits; FDA approved; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Profiling; Genetic; Grant; Health; Hematopoietic; Hemorrhage; Homeostasis; Human; IL-13Ralpha1; IL4 gene; Immunity; In Situ; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Intervention; Investigation; Joints; Lead; Liquid substance; Macrophage; Macrophage Activation; Medial meniscus structure; Mediating; Mediator; Military Personnel; Molecular; Mus; Myeloid Cells; Osteoblasts; Osteoclasts; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Play; Production; Rehabilitation Outcome; Rehabilitation therapy; Reporter; Research; Role; STAT6 gene; Sampling; Serum; Severities; Signal Transduction; Synovial Fluid; Testing; Th2 Cells; Therapeutic; Tissues; Tranexamic Acid; Translating; Translations; Veterans; candidate identification; cell type; cytokine; healing; in vivo; interleukin-13 receptor; joint injury; mast cell; military veteran; mouse model; pharmacologic; predictive marker; prevent; receptor; reduce symptoms; response; success; targeted agent; therapeutic candidate

Many Veterans and civilians sustain traumatic joint injuries, which frequently lead to joint dysfunction and development of osteoarthritis (OA). Existing treatments for joint injury and OA only alleviate symptoms, and are ineffective in promoting healing or preventing OA. Increasing evidence implicates “low-grade” inflammation following joint injury in development of OA. A better understanding of the underlying inflammatory mechanisms and identification of pharmacologic agents that target these mechanisms could transform care for military personnel, Veterans, and civilians with traumatic joint injuries and/or that are developing OA. Our preliminary studies suggest that Type II immunity and the IL-4/IL-13 inflammatory axis are dysregulated in OA. In this proposal, we aim to elucidate the roles of Type II immunity and the IL-4/IL-13 axis in the development of OA. Type II immunity and the IL-4/IL-13 inflammatory axis have been widely implicated in atopic diseases, such as asthma, but have not been extensively studied in the context of OA. We found that IL-4 is downregulated, while IL-13 levels are elevated, in the synovial fluids of individuals with OA. Our findings showed that genetic deficiency in IL-4 leads to more severe OA in mice after destabilization of the medial meniscus (DMM), while IL-13 may promote OA and thereby play an opposing role. Our in vitro studies showed IL-13 induces pathogenic activation of osteoblasts and fibroblasts; while IL-4 promotes protective M2 macrophage phagocytosis of pro-inflammatory cartilage debris and inhibits activation of osteoclasts. We found that pharmacologic inhibition of mast cells, which are major producers of IL-13, prevented OA in mice. Nevertheless, important questions remain about the mechanisms through which the IL-4/IL-13 axis mediates inflammatory responses following joint injury and in OA. We hypothesize that IL-4 and IL-13 mediate distinct responses in different cell types by signaling through the type-I or type-II cellular receptors, respectively. We hypothesize that following joint injury dysregulated activation of mast cells, basophils, ILC2 cells, and/or Th2 cells results in the production of IL-13. Further, we hypothesize that dysregulated IL-4/IL-13 expression leads to activation of osteoblasts and fibroblasts, loss of osteoclast inhibition, and dysregulated macrophage polarization. Finally, we hypothesize that, together, these changes disrupt homeostasis following joint injury or other insult and lead to development of OA. To test these hypotheses, Aim 1 will characterize the role of Type II immunity in the development of OA through analysis of the IL-4 and IL-13-producing cell types in OA synovial and infrapatellar fat pad tissues, and by analyzing in vivo the contributions of these cell types to OA development. Aim 2 will investigate the molecular mechanisms by which IL-4 and IL-13 regulate protective and pathogenic cellular responses in macrophages, osteoclasts, osteoblasts, synovial fibroblasts, and chondrocytes that contribute to OA. Aim 3 will identify blood biomarkers predictive of OA and the severity of OA. Aim 4 will genetically and pharmacologically target the IL-4/IL-13 pathway to prevent OA following DMM in mice. Importantly, Aim 4 will focus on FDA- approved drugs that target the IL-4/IL-13 axis, thereby providing a path for rapid translation and evaluation of promising candidates for efficacy in preventing OA in humans. If successful, the proposal will elucidate the role of Type II immunity and the IL-4/IL-13 inflammatory axis in the development of OA, and identify candidate therapeutics that can be rapidly translated into clinical trials to evaluate their ability to prevent or treat OA.

许多退伍军人和平民维持创伤性关节伤害，这经常导致联合功能障碍，并且 骨关节炎（OA）的发展。现有的关节损伤治疗方法，OA仅减轻症状，并且是 在促进愈合或预防OA方面无效。越来越多的证据暗示“低级”炎症 在OA发育中联合伤害之后。更好地了解潜在的炎症机制 并确定针对这些机制的药物可以改变军事护理 遭受创伤性关节伤害和/或正在发展OA的人员，退伍军人和平民。我们的初步 研究表明，II型免疫力和IL-4/IL-13炎症轴在OA中失调。在这个 提案，我们旨在阐明II型免疫力和IL-4/IL-13轴在OA发展中的作用。 II型免疫力和IL-4/IL-13炎症轴已广泛与特应疾病有关，例如 哮喘，但在OA的背景下尚未广泛研究。我们发现IL-4被下调，而 在OA的个体的滑液中，IL-13水平升高。我们的发现表明遗传 IL-4的不足会导致培养基弯面液（DMM）稳定后的小鼠更严重的OA，而 IL-13可能会促进OA，从而发挥反对作用。我们的体外研究表明IL-13的影响 成骨细胞和成纤维细胞的致病激活；而IL-4促进保护性M2巨噬细胞 促炎软骨碎片的吞噬作用并抑制破骨细胞的激活。我们发现 肥大细胞的药理抑制是IL-13的主要生产国，可预防小鼠的OA。 然而，关于IL-4/IL-13轴媒体的机制仍然存在重要问题 关节损伤和OA后的炎症反应。我们假设IL-4和IL-13媒体不同 通过通过I型或II型细胞接收器发出信号，在不同的细胞类型中的响应。我们 假设关节损伤后，肥大细胞，嗜碱性粒细胞，ILC2细胞和/或TH2的激活失调 细胞导致IL-13的产生。此外，我们假设失调的IL-4/IL-13表达导致 为了激活成骨细胞和成纤维细胞，损失破骨细胞抑制和失调的巨噬细胞 极化。最后，我们假设这些变化在联合受伤或 其他侮辱并导致OA的发展。 为了检验这些假设，AIM 1将表征II型免疫在OA发展中的作用 通过分析OA滑膜和基型脂肪垫组织中IL-4和IL-13产生的细胞类型，以及 通过分析体内这些细胞类型对OA发育的贡献。 AIM 2将调查 IL-4和IL-13调节受保护和致病性细胞反应的分子机制 巨噬细胞，破骨细胞，成骨细胞，滑膜成纤维细胞和软骨细胞会导致OA。目标3意志 确定对OA和OA严重程度的血液生物标志物。 AIM 4将一般和药品 靶向IL-4/IL-13途径，以防止小鼠DMM后OA。重要的是，AIM 4将专注于FDA- 针对IL-4/IL-13轴的批准药物，从而为快速翻译和评估提供了一条路径 有希望的候选人可以预防人类OA的效率。如果成功，该提议将阐明角色 OA发育中II型免疫力和IL-4/IL-13炎症轴 可以迅速转化为临床试验以评估其预防或治疗OA的能力的治疗剂。