Investigating the IL-4/13 Axis in Osteoarthritis

研究骨关节炎中的 IL-4/13 轴

• 批准号: 9891690
• 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/9891690
• 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; 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， 骨关节炎（OA）的发展。关节损伤和OA的现有治疗仅缓解症状， 对促进愈合或预防OA无效。越来越多的证据表明存在“低度”炎症 在OA的发展中关节损伤后。更好地了解潜在的炎症机制 并确定针对这些机制的药物制剂可以改变军事护理 患有创伤性关节损伤和/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型免疫和IL-4/IL-13炎性轴在OA中失调。在这 因此，我们的目的是阐明II型免疫和IL-4/IL-13轴在OA发展中的作用。 II型免疫和IL-4/IL-13炎性轴已广泛涉及特应性疾病，如 哮喘，但尚未在OA背景下进行广泛研究。我们发现IL-4下调，而 在患有OA的个体的滑液中，IL-13水平升高。我们的研究结果表明， 在内侧半月板（DMM）不稳定后，IL-4的缺乏导致小鼠中更严重的OA，而 IL-13可能促进OA，从而发挥相反的作用。我们的体外研究表明IL-13诱导 成骨细胞和成纤维细胞的致病性活化;而IL-4促进保护性M2巨噬细胞 吞噬促炎软骨碎片并抑制破骨细胞的活化。我们发现 肥大细胞是IL-13的主要产生者，对肥大细胞的药理学抑制可预防小鼠中的OA。 然而，关于IL-4/IL-13轴介导的机制仍然存在重要的问题。 关节损伤后的炎症反应和OA。我们假设IL-4和IL-13介导了不同的 通过分别通过I型或II型细胞受体的信号传导，在不同细胞类型中产生反应。我们 假设关节损伤后肥大细胞、嗜碱性粒细胞、ILC 2细胞和/或Th 2活化失调 细胞导致IL-13的产生。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活化、破骨细胞抑制的丧失和巨噬细胞失调 极化最后，我们假设，这些变化共同破坏了关节损伤后的稳态， 其他损伤并导致OA的发展。 为了验证这些假设，目标1将描述II型免疫在OA发展中的作用 通过分析OA滑膜和髌下脂肪垫组织中产生IL-4和IL-13的细胞类型， 通过分析体内这些细胞类型对OA发展的贡献。目标2将调查 IL-4和IL-13调节保护性和致病性细胞应答的分子机制 巨噬细胞、破骨细胞、成骨细胞、滑膜成纤维细胞和软骨细胞，这些细胞促成OA。目标3将 确定预测OA和OA严重程度的血液生物标志物。目标4将遗传和遗传 靶向IL-4/IL-13通路以预防小鼠DMM后OA。重要的是，目标4将侧重于FDA- 靶向IL-4/IL-13轴的获批药物，从而为快速翻译和评估 在预防人类OA中有效的有希望的候选物。如果成功，该提案将阐明 II型免疫和IL-4/IL-13炎症轴在OA发展中的作用，并确定候选 这些药物可以迅速转化为临床试验，以评估其预防或治疗OA的能力。