Restitution of Lubrication in ACL Deficient Joints Preventing Wear

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。几项大型纵向人群研究基于患者病史和回顾性数据收集工具支持这一观察结果。然而，识别有进展风险的患者的努力有限。我们假设患者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。这些患者出现在急诊科，表现为急性外伤性滑膜炎（TS）继发于结构缺陷，如外伤后急性前交叉韧带（ACL）损伤。免疫学和力学分析都证明了在人类和动物模型中损伤后滑液中润滑油的可变缺乏。最近对润滑素（PRG4）缺失小鼠的观察支持了软骨磨损增强的可能结果，这些小鼠出生时关节表面正常，相比之下，负重后表面颤动开始。润滑素和表面带蛋白（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酶表达，蛋白酶易分解代谢润滑素/SZP。在确定引发这种破坏的酶方面已经取得了进展。我们提出了3个相互关联的特定目标，涉及前交叉韧带损伤患者和相应的动物模型，以更好地了解滑膜稳态，因为它与润滑和扩展软骨保护有关。目的1：研究哺乳动物关节前交叉韧带损伤伴轻度炎症对润滑素介导的润滑机制的早期影响。目的2：确定通过使用TNF-a抑制剂阻断TNF-a的作用是否能部分恢复前交叉韧带损伤后腹泻关节的润滑能力。目的3：分析急性前交叉韧带损伤患者的滑液抽吸液中的润滑素水平、润滑素降解产物及其与IL-1b和TNF-a水平的关系。公共卫生相关性：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，由于润滑素的分解代谢，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慢性关节疾病的风险。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尺度上运动的特征。我们还假设，通过使用TNF-a抑制剂（Enbrel）阻断TNF-a的作用，可以部分恢复前交叉韧带损伤后腹泻关节的润滑能力。

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.