Restitution of Lubrication in ACL Deficient Joints Preventing Wear

ACL 缺陷关节的润滑恢复防止磨损

• 批准号: 7615686
• 负责人: GREGORY D. JAY
• 金额: $ 16.97万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615686
• 关键词: Accident and Emergency department; Acute; Address; Animal Model; Anterior Cruciate Ligament; Arthritis; Aspirate substance; Biological Assay; Biological Markers; Biological Preservation; Birth; Cartilage; Catabolism; Cathepsins B; Chondrocytes; Chronic; Clinical; Collagen Fibril; Collagen Type II; Cysteine Protease; Data; Data Collection; Defect; Degenerative polyarthritis; Digestion; Electron Microscopy; Emergency Medicine; Emergency Situation; Enzymes; Etanercept; Failure; Fibroblasts; Friction; Homeostasis; Homologous Protein; Human; Hyaluronic Acid; Immunologics; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1; Intervention; Investigation; Joints; Knee; Knee Injuries; Knee joint; Knockout Mice; Leukocyte Elastase; Lubricants; Lubrication; Measures; Mechanics; Mediating; Metabolism; Movement; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Physicians; Play; Population; Population Study; Positioning Attribute; Primary Health Care; Process; Proteins; Provider; Public Health; Publishing; Rattus; Recording of previous events; Resolution; Risk; Risk Factors; Role; Secondary to; Serine Protease; Slide; Speed; Surface; Symptoms; Synovial Fluid; Synovitis; TNF gene; Techniques; Therapeutic; Time; Trauma; Viscosity; Weight-Bearing state; Work; articular cartilage; base; clinically relevant; cytokine; inhibitor/antagonist; injured; instrument; joint injury; ligament injury; lubricin; nanoscale; novel; population based; prevent; research study

DESCRIPTION (provided by applicant): 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 chronic joint complaints. These patients present to emergency departments and manifest an acute traumatic synovitis (TS) secondary to structural defects such as acute anterior cruciate ligament (ACL) injuries following trauma. Both immunologic and mechanical assays have documented a variable lack of lubricin in synovial fluid following injury in both humans and animal models. The presumable result of enhanced cartilaginous wear is supported by recent observations in lubricin (PRG4) null mice which have a normal articular surface at birth and, by contrast, surface fibrillation after weight bearing begins. Lubricin and superficial zone protein (SZP) are the boundary lubricants of articular cartilage- a lubrication mechanism which arises in the absence of viscosity. Diarthrodial joint inflammation results in protease expression which easily catabolizes lubricin/SZP. Progress has been made in identifying the enzymes which initiate this destruction. We propose 3 interconnecting specific aims engaging patients with ACL injuries and a corresponding animal model to better understand synovial homeostasis as it relates to lubrication and by extension chondroprotection. Aim 1: To investigate the early effects of an ACL injury accompanied by mild inflammation on lubricating mechanisms mediated by lubricin in a mammalian joint. Aim 2: Determine if blocking the effects of TNF-a through the administration of a TNF-a inhibitor partially restores the lubricating ability of diarthrodial joints following ACL injury. Aim 3: Synovial fluid aspirates from patients with acute ACL injuries will be analyzed for lubricin levels, lubricin degradation products and its relationship to IL-1b and TNF-a levels. PUBLIC HEALTH RELEVENCE: Injury is a well-established risk factor in the pathogenesis of osteoarthritis (OA). We hypothesize that mammalian joints with acute knee injuries and resultant inflammation are at risk for chronic joint complaints as a result of catabolism of lubricin. This protein serves to protect cartilage from the high load and slow sliding speeds, which characterize movements of these joints at the nanoscale. We also hypothesize that blocking the effects of TNF-a through the administration of a TNF-a inhibitor (Enbrel) partially restores the lubricating ability of diarthrodial joints following ACL injury.

描述（由申请方提供）：损伤是骨关节炎（OA）发病机制中公认的风险因素。基于患者病史和回顾性数据收集工具，几项大型纵向人群研究支持这一观察结果。然而，识别有进展风险的患者的努力有限。我们认为，急性膝关节损伤和由此产生的炎症患者有慢性关节疾病的风险。这些患者到急诊室就诊，表现为继发于结构缺陷的急性创伤性滑膜炎（TS），如创伤后急性前交叉韧带（ACL）损伤。免疫学和机械测定都记录了人类和动物模型损伤后滑液中润滑素的可变缺乏。增强软骨磨损的推测结果得到了最近在润滑素（PRG 4）缺失小鼠中的观察结果的支持，这些小鼠在出生时具有正常的关节表面，相比之下，在负重开始后具有表面纤维化。润滑素和表浅区蛋白（SZP）是关节软骨的边界润滑剂-一种在没有粘度的情况下产生的润滑机制。关节炎导致蛋白酶表达，其容易分解代谢润滑素/SZP。在鉴定启动这种破坏的酶方面已经取得了进展。我们提出了3个相互关联的具体目标，使ACL损伤患者和相应的动物模型参与进来，以更好地了解滑膜稳态，因为它与润滑和软骨保护有关。目标1：研究伴有轻度炎症的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。目标二：确定通过给予TNF-α抑制剂阻断TNF-α的作用是否部分恢复ACL损伤后关节的润滑能力。目标3：将分析急性ACL损伤患者的滑液抽吸物的润滑素水平、润滑素降解产物及其与IL-1b和TNF-α水平的关系。 公共卫生救济：损伤是骨关节炎（OA）发病机制中公认的危险因素。我们假设，哺乳动物关节急性膝关节损伤和由此产生的炎症是在慢性关节疾病的风险，作为润滑素的catastrophin的结果。这种蛋白质用于保护软骨免受高负荷和缓慢滑动速度的影响，这是这些关节在纳米级运动的特征。我们还假设，通过给予TNF-α抑制剂（Enbrel）阻断TNF-α的作用，部分恢复ACL损伤后关节的润滑能力。