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: 7434907
• 负责人: GREGORY D. JAY
• 金额: $ 19.56万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434907
• 关键词: Accident and Emergency department; Acute; Address; Animal Model; Anterior Cruciate Ligament; 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; Depth; Digestion; Electron Microscopy; Elevation; Emergency Medicine; Emergency Situation; End Point; Endopeptidases; 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; lubricin; nanoscale; novel; 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（由申请人提供）：伤害是骨关节炎发病机理（OA）的良好危险因素。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了这一观察结果。但是，识别有进展风险的患者的努力受到限制。我们认为急性膝关节受伤和导致炎症患者有慢性关节投诉的风险。这些患者出现在急诊室，表现出继发于结构缺陷的急性外伤滑膜炎（TS），例如创伤后急性前交叉韧带（ACL）损伤。免疫学和机械测定都证明了人类和动物模型受伤后滑液中缺乏润滑剂。润滑剂（PRG4）无效小鼠的最新观察结果支持了增加的软骨磨损的可能结果，这些无小鼠在出生时具有正常的关节表面，相比之下，负重轴承后的表面纤维化开始。润滑剂和表面蛋白（SZP）是关节软骨的边界润滑剂 - 在没有粘度的情况下会产生的润滑机制。腹膜内关节炎症会导致蛋白酶表达，从而很容易分解润滑剂/SZP。在识别启动这种破坏的酶方面取得了进展。我们提出了3种互连的特定目标，使患有ACL损伤的患者和相应的动物模型可以更好地理解滑膜稳态，因为它与润滑和扩展软骨保护有关。目标1：研究ACL损伤的早期作用，伴随着轻度炎症对哺乳动物关节中润滑剂介导的润滑机制。 AIM 2：确定通过给予TNF-A抑制剂阻断TNF-A的影响是否部分恢复了ACL损伤后腹膜关节的润滑能力。 AIM 3：将分析来自急性ACL损伤患者的滑液，以分析润滑剂水平，润滑剂降解产物及其与IL-1B和TNF-A水平的关系。 公共卫生相关性：伤害是骨关节炎发病机理（OA）的公认危险因素。我们假设患有急性膝关节损伤的哺乳动物关节和导致的炎症是由于润滑剂的分解代谢而受到慢性关节投诉的风险。该蛋白质可保护软骨免受高载荷和缓慢的滑动速度，这表征了纳米级的这些关节的运动。我们还假设，通过施用TNF-A抑制剂（ENBREL）阻止TNF-A的影响会部分恢复ACL损伤后腹膜关节的润滑能力。