Investigating the IL-4/13 Axis in Osteoarthritis

研究骨关节炎中的 IL-4/13 轴

• 批准号: 10092814
• 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/10092814
• 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