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

基本信息

批准号：
10672163
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
项目类别：
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/10672163
关键词：
Acceleration 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 Immunoprecipitation Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Injury Intervention Joints Lead Letters Liquid substance Mass Spectrum Analysis Medial meniscus structure Mediating Mediator Military Personnel Monitor Mus Outcome Pathogenesis Pathology Pathway interactions Phenotype Phosphorylation Prevention Process Proliferating 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 Traumatic Arthropathy Tryptase Tyrosine Kinase Inhibitor Veterans Western Blotting blood-based biomarker candidate identification cohort crosslink efficacy evaluation experience functional outcomes gait examination healing improved inhibitor joint injury mast cell military veteran mouse model novel marker overexpression pharmacologic post-trauma prevent reduce symptoms response success targeted agent targeted treatment therapeutic target

项目摘要

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遭受外伤性关节损伤，这往往导致康复效果不佳损伤关节的结果、关节功能障碍和骨关节炎 (OA) 的发展。关节损伤和OA只能缓解症状，对促进愈合或预防OA无效。越来越多的证据表明关节损伤后的“低度”炎症会导致康复结果不佳，以及对创伤后 OA 的最终发展有更好的了解。针对失调途径的药物机制和鉴定可能会改变为患有关节外伤的军事人员、退伍军人和平民提供护理和康复服务。初步研究表明肥大细胞在介导关节炎症反应中发挥着关键作用损伤和促进创伤后 OA 的发展在本提案中，我们旨在阐明 OA 的作用。肥大细胞在关节损伤后康复效果不佳以及创伤后骨关节炎的发展中发挥着重要作用。在 OA 滑膜以及创伤后非 OA 关节中检测到肥大细胞，并且能够产生我们发现肥大细胞介质过度表达，包括肥大细胞介质。关节损伤或 OA 个体的滑膜和液体中的细胞特异性类胰蛋白酶数据来自两个人。小鼠模型表明，肥大细胞的缺乏减弱了 OA 相关的病理，而肥大细胞的植入肥大细胞恢复了这种表型。肥大细胞激活的药理学抑制证实了这些结果。我们的体外研究表明，类胰蛋白酶诱导 OA 发病机制中不可或缺的几个过程：退化人类软骨、关节软骨细胞凋亡以及促炎症反应和增殖此外，我们发现 IgE 信号由 FcεRI、Syk 和组胺释放介导。然而，重要的问题仍然存在。关于关节创伤后肥大细胞激活的上游机制以及在 OA 中的作用 IgE，以及针对肥大细胞途径或产品是否可以改善康复并预防 OA。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，从而损害康复并加速 OA 的发展。损伤引起的关节和软骨分解产物会导致 IgE 反应和/或产生激活肥大细胞的 HRF，并且可以鉴定生物标志物来指导药理学靶向肥大细胞以促进成功康复并预防创伤后骨关节炎的发展。为了检验这些假设，在目标 1 中，我们建议描述肥大细胞激活、脱颗粒和人类关节损伤后、康复和 OA 中的生物标志物在目标 2 中，我们将表征 IgE。在目标 3 中，我们将确定针对关节损伤、康复和 OA 的治疗策略。肥大细胞途径可改善康复结果并预防关节损伤后继发性 OA 重要的是，Aim 3 将重点关注 FDA 批准的内侧半月板 (DMM) 小鼠模型。靶向肥大细胞，从而为快速翻译和评估有前途的细胞提供途径促进成功康复结果和预防发展的功效候选人如果成功，该提案将阐明肥大细胞的作用。和 IgE 在关节损伤后康复结果和 OA 发展中的作用（目标 1 和 2），建立生物标记物可识别可能患有肥大细胞介导的不良康复结果的个体和创伤后 OA（目标 1 和 2），并确定针对肥大的候选药物干预措施细胞促进成功康复和最佳功能结果（目标 3）。