Investigating the IL-4/13 Axis in Osteoarthritis

研究骨关节炎中的 IL-4/13 轴

• 批准号: 10438519
• 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/10438519
• 关键词: Anti-Inflammatory Agents; Asthma; Award; Basophils; Biological Markers; Blood; Bone remodeling; Caring; Cartilage; Cells; Chondrocytes; Clinical; Clinical Trials; 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 Activation; Medial meniscus structure; Mediating; Mediator of activation protein; Military Personnel; Molecular; Mus; Myeloid Cells; Osteoblasts; Osteoclasts; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Pharmacology; 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; base; cell type; cytokine; healing; in vivo; interleukin-13 receptor; joint injury; macrophage; mast cell; military veteran; mouse model; 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遭受创伤性关节损伤，这经常导致关节功能障碍和 骨关节炎(OA)的发展。现有的关节损伤和骨性关节炎的治疗方法只能缓解症状，而且 在促进愈合或预防骨性关节炎方面效果不佳。越来越多的证据表明“低度”炎症 关节损伤后发生的骨性关节炎。更好地了解潜在的炎症机制 而针对这些机制的药理学药物的识别可能会改变军事保健 患有创伤性关节损伤和/或患有骨性关节炎的人员、退伍军人和平民。我们的预赛 研究表明，骨性关节炎患者存在II型免疫功能紊乱和IL-4/IL-13炎性轴功能紊乱。在这 我们的目的是阐明II型免疫和IL-4/IL-13轴在骨性关节炎发生发展中的作用。 II型免疫和IL-4/IL-13炎症轴广泛参与特应性疾病，如 哮喘，但还没有在骨性关节炎的背景下广泛研究。我们发现IL-4表达下调，而 骨性关节炎患者的滑液中IL-13水平升高。我们的发现表明，基因 IL-4缺乏导致小鼠内侧半月板(DMM)失稳后更严重的骨关节炎，而 IL-13可能促进骨性关节炎，从而发挥相反的作用。我们的体外研究表明IL-13可以诱导 成骨细胞和成纤维细胞的致病活性；而IL-4促进保护性M2巨噬细胞 吞噬促炎软骨碎屑并抑制破骨细胞的激活。我们发现 肥大细胞是IL-13的主要产生者，对肥大细胞的药物抑制可以预防小鼠的骨性关节炎。 然而，关于IL-4/IL-13轴的调节机制仍然存在重要的问题 关节损伤后和骨性关节炎的炎症反应。我们假设IL-4和IL-13分别在 不同细胞类型的反应分别通过I型或II型细胞受体发出信号。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 细胞产生IL-13。此外，我们假设IL-4/IL-13表达失调导致 成骨细胞和成纤维细胞的激活，破骨细胞抑制的丧失和巨噬细胞的失调 极化。最后，我们假设，这些变化共同破坏了关节损伤后的体内平衡。 其他侮辱和导致办公自动化发展的。 为了验证这些假说，目标1将描述II型免疫在骨性关节炎发生发展中的作用 通过分析骨性关节炎滑膜和髌下脂肪垫组织中产生IL-4和IL-13的细胞类型，以及 通过体内分析这些细胞类型对骨性关节炎发生的贡献。目标2将调查 IL-4和IL-13调节细胞保护性和致病性反应的分子机制 巨噬细胞、破骨细胞、成骨细胞、滑膜成纤维细胞和软骨细胞对骨性关节炎有贡献。目标3将 确定预测骨性关节炎和骨性关节炎严重程度的血液生物标志物。Aim 4将在遗传学和药理学上 靶向IL-4/IL-13通路预防小鼠DMM后骨性关节炎。重要的是，Aim 4将专注于FDA- 已批准的靶向IL-4/IL-13轴的药物，从而为快速翻译和评估 有望成为预防人类骨性关节炎的有效候选药物。如果成功，该提案将阐明这一角色 探讨II型免疫和IL-4/IL-13炎性轴在骨性关节炎发生发展中的作用，并确定候选因子 可迅速转化为临床试验的治疗药物，以评估其预防或治疗骨性关节炎的能力。