Targeting Mast Cells in Post-Traumatic Joint Rehabilitation and Osteoarthritis

在创伤后关节康复和骨关节炎中靶向肥大细胞

• 批准号: 10284924
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284924
• 关键词: Antigens; Apoptosis; Attenuated; Biological Markers; Blood; Caring; Cartilage; Cell Count; Cell Degranulation; Cellular Assay; Chondrocytes; Data; Degenerative polyarthritis; Development; Drug Targeting; Electron Microscopy; Engraftment; Enzyme-Linked Immunosorbent Assay; Evaluation; FDA approved; Fibroblasts; Functional disorder; Gait; Goals; Health; Histamine Production; Human; IgE; Imatinib; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Joints; Lead; Letters; Liquid substance; Mass Spectrum Analysis; Medial meniscus structure; Mediating; Mediator of activation protein; Military Personnel; Monitor; Mus; Outcome; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phenotype; Prevention; Process; Proteins; Recovery; Rehabilitation Outcome; Rehabilitation therapy; Research; Role; SYK gene; Sampling; Serum; Signal Transduction; Synovial Fluid; Synovial Membrane; TPT1 gene; Testing; Therapeutic; Tissues; Translating; Translations; Tryptase; Tyrosine Kinase Inhibitor; Veterans; base; blood-based biomarker; cohort; crosslink; efficacy evaluation; experience; functional outcomes; gait examination; healing; improved; inhibitor; joint injury; mast cell; military veteran; mouse model; novel marker; overexpression; post-trauma; prevent; reduce symptoms; response; success; targeted agent; targeted treatment; therapeutic target

Many Veterans and civilians sustain traumatic joint injuries, which frequently lead to poor rehabilitation outcomes, joint dysfunction, and development of osteoarthritis (OA) in the injured joint. 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 poor rehabilitation outcomes, and in the eventual development of post-traumatic OA. A better understanding of the underlying inflammatory mechanisms and identification of pharmacologic agents that target the dysregulated pathways could transform the care and rehabilitation for military personnel, Veterans, and civilians with traumatic joint injuries. Our preliminary studies suggest a critical role for mast cells in mediating inflammatory responses following joint injury and in promoting the development of post-traumatic OA. In this proposal, we aim to elucidate the roles of mast cells in poor rehabilitation outcomes following joint injury and in the development of post-traumatic OA. Mast cells are detected in OA synovium as well as in post-trauma non-OA joints, and are capable of producing pro-inflammatory and degradative mediators. We found overexpression of mast cell mediators, including mast cell-specific tryptases, in synovial membranes and fluids from individuals with joint injury or OA. Data from two mouse models indicated that lack of mast cells attenuated OA-related pathologies, whereas engraftment of mast cells restored this phenotype. Pharmacologic inhibition of mast cell activation confirmed these results. Our in vitro studies showed that tryptase induces several processes integral to OA pathogenesis: degeneration of human cartilage, apoptosis of articular chondrocytes, and pro-inflammatory responses and proliferation of synovial fibroblasts. Further, we found that IgE signaling mediated by FcεRI, Syk, and histamine-releasing factor (HRF) is involved in the pathogenesis of post-traumatic OA. Nevertheless, important questions remain about the upstream mechanisms underlying mast cell activation following joint trauma and in OA, the role of IgE, and whether targeting mast cell pathways or products might improve rehabilitation and prevent OA. We hypothesize that following joint injury, IgE-mediated activation of mast cells involving FcεRI, Syk, and HRF promotes inflammation, which impairs rehabilitation and accelerates the development of OA. Further, we hypothesize that injury-induced joint and cartilage breakdown products lead to an IgE response and/or production of HRF that activates mast cells, and that biomarkers can be identified to guide pharmacologic targeting of mast cells to promote successful rehabilitation and prevent the development of post-traumatic OA. To test these hypotheses, in Aim 1, we propose to characterize mast cell activation, degranulation, and biomarkers in human joints post-injury, in rehabilitation, and in OA. In Aim 2, we will characterize the IgE response in joint injury, rehabilitation, and OA. In Aim 3, we will identify strategies that pharmacologically target mast cell pathways to improve rehabilitation outcomes and to prevent secondary OA following joint injury in the destabilization of the medial meniscus (DMM) mouse model. Importantly, Aim 3 will focus on FDA-approved drugs that target mast cells, thereby providing a path for rapid translation and evaluation of promising candidates for efficacy in promoting successful rehabilitation outcomes and preventing development of secondary OA following joint injury in humans. If successful, the proposal will elucidate the roles of mast cells and IgE in rehabilitation outcomes and development of OA following joint injury (Aims 1 and 2), establish biomarkers to identify individuals who are likely to suffer from mast-cell-mediated poor rehabilitation outcomes and post-traumatic OA (Aims 1 and 2), and identify candidate pharmacologic interventions that target mast cells to promote successful rehabilitation and optimal functional outcomes (Aim 3).

许多退伍军人和平民维持创伤性联合伤害，这经常导致康复不佳 受伤关节中的结局，关节功能障碍和骨关节炎（OA）的发展。现有的治疗方法 联合损伤和OA仅减轻症状，并且在促进愈合或预防OA方面无效。 越来越多的证据表明，在康复结果不良后，共同受伤后的“低度”炎症， 并在创伤后OA的发展中发展。更好地理解潜在的炎症 靶向失调途径的机制和鉴定药物可以转化 对军事人员，退伍军人和平民的护理和康复，遭受创伤的联合伤害。我们的 初步研究表明，肥大细胞在介导关节后介导炎症反应中的关键作用 伤害并促进创伤后OA的发展。在此提案中，我们旨在阐明 联合损伤和创伤后OA的发展后，康复结果不良的肥大细胞。 在OA滑膜以及创伤后的非OA关节中检测到肥大细胞，并能够产生 亲炎和降解介体。我们发现肥大细胞介质的过表达，包括桅杆 来自关节损伤或OA的个体的滑膜和流体中的细胞特异性胰蛋白酶酶。来自两个的数据 小鼠模型表明，缺乏肥大细胞会减弱与OA相关的病理，而植入 肥大细胞恢复了这种表型。肥大细胞活化的药理抑制证实了这些结果。 我们的体外研究表明，胰蛋白酶诱导了OA发病机理不可或缺的几个过程：变性 人体软骨，关节软骨细胞的凋亡以及促炎反应和增生 滑膜成纤维细胞。此外，我们发现由FcεRI，SYK和组胺释放介导的IgE信号传导 因子（HRF）参与创伤后OA的发病机理。然而，重要的问题仍然存在 关于关节创伤后和OA，关于肥大细胞激活的上游机制，在OA中的作用 IgE以及靶向肥大细胞途径还是产品是否可以改善康复并预防OA。我们 假设在关节损伤后，IgE介导的肥大细胞激活涉及FCεRI，SYK和HRF 促进炎症，这会损害康复并加速OA的发展。此外，我们 假设受伤引起的关节和软骨崩溃产物会导致IgE响应和/或 激活肥大细胞的HRF的产生，可以鉴定出生物标志物来引导药理学 靶向肥大细胞以促进成功的康复并防止创伤后OA的发展。 为了检验这些假设，在AIM 1中，我们建议表征肥大细胞激活，脱粒和 康复后和OA中的人类关节中的生物标志物。在AIM 2中，我们将描述IgE 关节损伤，康复和OA的反应。在AIM 3中，我们将确定药物针对的策略 肥大细胞途径改善康复结果并防止在联合损伤后进行次级OA 内侧半月板（DMM）小鼠模型的不稳定。重要的是，AIM 3将专注于FDA批准 靶向肥大细胞的药物，从而为快速翻译和评估提供了一条路径 候选人在促进成功的康复结果和防止发展方面的效率 人类联合受伤后的次要OA。如果成功，该提案将阐明肥大细胞的作用 和IGE在联合受伤后的康复结果和OA的发展（目标1和2）中，建立 生物标志物识别可能患有桅杆介导的康复结果不佳的人 和创伤后的OA（目标1和2），并确定针对桅杆的候选药物学干预措施 细胞促进成功的康复和最佳功能结果（AIM 3）。