RI COBRE: ASSESSMENT OF CHONDROPROTECTION IN ACL INJURIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在骨关节炎的发病机制中，损伤是一个公认的危险因素。基于病史和回溯性数据收集工具的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早期磨损和关节损伤的风险。 由于软骨失去了润滑能力。这些患者出现在急诊科，表现为继发于急性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。这些患者的特点是：1)II型胶原碎片的释放与早期软骨破坏一致，2)消化润滑油(PRG4)，缺乏润滑能力，3)没有退行性关节疾病的病史。我们认为，炎症导致润滑剂的破坏，伴随着软骨纤颤和慢性症状，这是基于人群的观察结果的早期骨关节炎归因于关节损伤。旨在解决一些最早引起骨性关节炎的因素的干预措施可以是急诊科(ED)或以初级保健为基础。关节损伤后也可能有一个关键的时间窗口，当限制这一过程的范围可能是主要的治疗终点时。目的1：探讨前交叉韧带损伤对润滑素介导的哺乳动物关节润滑机制的早期影响。假设：一个ACL 大鼠膝关节损伤导致润滑剂代谢改变，导致关节摩擦系数(U)升高。这会导致关节表面的永久性损坏或关节无法恢复到0.001的低m。目标2：通过给药阻断肿瘤坏死因子-α的影响 肿瘤坏死因子-α抑制剂可部分恢复前交叉韧带损伤后腹股沟关节的润滑能力。假设：肿瘤坏死因子-α在前交叉韧带损伤后的润滑脂代谢变化中起重要作用。阻断肿瘤坏死因子-α的作用可以保护关节的润滑性，并限制关节磨损。目的：检测急性前交叉韧带损伤患者滑液中IL-1和TNF-α的含量。假设：临床吸液中的润滑剂浓度与分解代谢细胞因子之间存在负相关关系，这可以被描述为轻度炎症状态。

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 nstruments. 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 populationbased 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 (u) of the joint. This results in permanent damage to articulating surfaces or failure of the joint to return to a low m of 0.001. Aim 2: 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. Hypothesis: TNF-a play a significant role in mediating changes in lubricin metabolism following ACL injury. Blocking the effects of TNF-a 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-a. Hypothesis: An inverse relationship exists between lubricin concentration and catabolic cytokines in clinical aspirates which can be characterized as a mild inflammatory state.