RI COBRE: ASSESSMENT OF CHONDROPROTECTION IN ACL INJURIES

RI COBRE：ACL 损伤中软骨保护的评估

• 批准号: 8168038
• 负责人: GREGORY D. JAY
• 金额: $ 19.61万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168038
• 关键词: Accident and Emergency department; Acute; Address; Anterior Cruciate Ligament; Aspirate substance; Cartilage; Centers of Research Excellence; Chronic; Clinical; Collagen Type II; Computer Retrieval of Information on Scientific Projects Database; Data Collection; Defect; Degenerative polyarthritis; Digestion; Failure; Friction; Funding; Grant; Inflammation; Inflammatory; Injury; Institution; Interleukin-1; Intervention; Joints; Knee Injuries; Knee joint; Lubrication; Mediating; Metabolism; Pathogenesis; Patients; Play; Population Study; Primary Health Care; Process; Rattus; Recording of previous events; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Secondary to; Source; Surface; Symptoms; Synovial Fluid; Synovitis; Therapeutic; Time; Trauma; United States National Institutes of Health; articular cartilage; base; cytokine; inhibitor/antagonist; instrument; joint injury; ligament injury; lubricin; population based

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Injury is a well established risk factor in the pathogenesis of osteoarthritis (OA). Several large longitudinal population studies support this observation based upon patient history and retrospective data collection instruments. However, efforts to identify patients at risk of progression have been limited. We posit that patients with acute knee injuries and resultant inflammation are at risk for early wear and damage to articular cartilage due to loss of lubricating ability. These patients present to emergency departments and manifest an acute traumatic synovitis (TS) secondary to acute structural defects such as acute anterior cruciate ligament (ACL) injuries following trauma. These patients are young and feature, 1) collagen type II fragment release consistent with early cartilage destruction, 2) digestion of lubricin (PRG4) and lack lubricating ability, and 3) do not have any history of degenerative joint disease. We argue that inflammation results in the destruction of lubricin, accompanied by the fibrillation of cartilage and chronic symptoms which underpin the population based observation of early OA attributable to joint injury. Interventions intended to address some of the earliest causative factors of OA could be emergency department (ED) or primary care based. There may also be a critical time window immediately after a joint injury when limiting the extent of this process could be a primary therapeutic endpoint. The aims are the following: Aim 1: To Investigate the Early Effects of an ACL Injury on Lubricating Mechanisms Mediated by Lubricin in a Mammalian Joint. Hypothesis: An ACL injury induced in rat knee joints results in changes to lubricin metabolism leading to an elevation of the coefficient of friction (¿) of the joint. This results in permanent damage to articulating surfaces or failure of the joint to return to a low ¿ of 0.001. Aim 2: Blocking the Effects of TNF-¿ Through the Administration of a TNF-¿ Inhibitor Partially Restores the Lubricating Ability of Diarthrodial Joints Following ACL Injury. Hypothesis: TNF-¿ play a significant role in mediating changes in lubricin metabolism following ACL injury. Blocking the effects of TNF-¿ preserves joint lubrication and limits joint wear. Aim 3: Synovial Fluid Aspirates from Patients with Acute ACL Injuries will be Analyzed for IL-1 and TNF-¿. Hypothesis: An inverse relationship exists between lubricin concentration and catabolic cytokines in clinical aspirates which can be characterized as a mild inflammatory state.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 损伤是骨关节炎（OA）发病机制中公认的危险因素。几项大型纵向人群研究根据患者病史和回顾性数据收集工具支持了这一观察结果。然而，识别有进展风险的患者的努力仍然有限。我们认为，患有急性膝关节损伤和由此产生的炎症的患者由于失去润滑能力而面临早期磨损和关节软骨损伤的风险。这些患者到急诊科就诊，表现为继发于急性结构缺陷（例如创伤后急性前十字韧带（ACL）损伤）的急性创伤性滑膜炎（TS）。这些患者很年轻，具有以下特征：1) II 型胶原片段释放与早期软骨破坏一致，2) 润滑素 (PRG4) 消化且缺乏润滑能力，3) 没有任何退行性关节病史。我们认为，炎症会导致润滑素的破坏，并伴有软骨颤动和慢性症状，这些症状支持基于人群的对关节损伤引起的早期 OA 的观察。旨在解决 OA 的一些最早致病因素的干预措施可以基于急诊科 (ED) 或初级保健。关节损伤后也可能存在一个关键时间窗口，此时可以限制该过程的程度 主要治疗终点。目标如下： 目标 1：研究 ACL 损伤对哺乳动物关节中润滑素介导的润滑机制的早期影响。假设：大鼠膝关节中诱导的 ACL 损伤会导致润滑素代谢发生变化，从而导致关节摩擦系数 (¿) 升高。这会导致关节表面永久性损坏或失效 联合返回到低 ¿ 0.001。目标 2：通过施用 TNF-¿ 抑制剂来阻断 TNF-¿ 的作用，部分恢复 ACL 损伤后关节的润滑能力。假设：TNF-¿ 在介导 ACL 损伤后润滑素代谢变化中发挥重要作用。阻断 TNF-¿ 的作用可以保持关节润滑并限制关节磨损。目标 3：对急性 ACL 损伤患者的滑液抽吸物进行 IL-1 和 TNF-¿ 分析。假设：临床抽吸物中润滑素浓度与分解代谢细胞因子之间存在负相关关系，可表征为轻度炎症状态。