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: 10025268
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025268
• 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/antagonist; 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遭受创伤性关节损伤，这往往导致难以康复