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)：损伤是骨关节炎(OA)发病机制中一个公认的危险因素。几项基于病史和回溯性数据收集工具的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一直有限。我们假设，急性膝关节损伤和由此产生的炎症的患者有慢性关节主诉的风险。这些患者出现在急诊科，表现为继发于结构缺陷的急性创伤性滑膜炎(TS)，例如创伤后的急性前十字韧带(ACL)损伤。免疫学和机械分析都证明，在人类和动物模型中，损伤后的滑液中都存在可变的润滑剂缺乏。最近在润滑素(PRG4)缺失的小鼠中观察到的增强软骨磨损的可能结果得到了支持，这些小鼠出生时关节表面正常，相比之下，开始负重后关节表面纤颤。润滑素和表面区蛋白(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。腹泻性关节炎症导致蛋白水解酶的表达，这很容易分解代谢润滑素/SZP。在鉴定引发这种破坏的酶方面已经取得了进展。我们提出了三个相互关联的特定目标，使前交叉韧带损伤患者参与进来，并建立相应的动物模型，以更好地了解滑膜动态平衡与润滑和软骨保护的关系。目的1：探讨伴有轻度炎症的前交叉韧带损伤对哺乳动物关节中润滑剂介导的润滑机制的早期影响。目的2：确定通过给予肿瘤坏死因子-α抑制剂阻断肿瘤坏死因子-α的作用是否能部分恢复前交叉韧带损伤后腹泻性关节的润滑能力。目的：分析急性前交叉韧带损伤患者滑液中润滑油水平、润滑油降解产物及其与IL-1b、TNF-α水平的关系。公共卫生报道：损伤是骨关节炎(OA)发病机制中一个公认的危险因素。我们假设，由于润滑剂的分解代谢，患有急性膝关节损伤和由此产生的炎症的哺乳动物关节有患慢性关节疾病的风险。这种蛋白质用来保护软骨免受高负荷和慢滑动速度的影响，这是这些关节在纳米尺度上运动的特征。我们还假设，通过给予肿瘤坏死因子-α抑制剂(Enbrel)阻断肿瘤坏死因子-α的影响，可以部分恢复前交叉韧带损伤后腹股沟关节的润滑能力。