RI COBRE: ASSESSMENT OF CHONDROPROTECTION IN ACL INJURIES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 损伤是骨关节炎（OA）发病机制中公认的危险因素。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由于失去润滑能力，有早期磨损和关节软骨损伤的风险。这些患者到急诊室就诊，表现为继发于急性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。这些患者年轻且特征为：1）II型胶原片段释放与早期软骨破坏一致，2）润滑素（PRG 4）消化且缺乏润滑能力，以及3）无任何退行性关节病史。我们认为，炎症导致润滑素的破坏，伴随着软骨纤维化和慢性症状，这支持了基于人群的观察早期OA归因于关节损伤。旨在解决OA的一些最早致病因素的干预措施可能是急诊科（艾德）或基于初级保健的干预措施。在关节损伤后，也可能有一个关键的时间窗口，此时可以限制该过程的程度。 主要治疗终点。其目标如下：目标1：研究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。假设：在大鼠膝关节中诱导的ACL损伤导致润滑素代谢的变化，从而导致关节摩擦系数（<$）的升高。这会导致关节面永久性损伤或关节面失效。 联合回到0.001的低点。目标二：通过给予TNF-α抑制剂阻断TNF-α的作用可部分恢复ACL损伤后关节的润滑能力。假设：TNF-α在调节ACL损伤后润滑素代谢的变化中起重要作用。阻断TNF-α的作用可以保护关节润滑并限制关节磨损。目的3：分析急性ACL损伤患者的滑液抽吸物中的IL-1和TNF-α。假设：在临床抽吸物中，润滑素浓度和分解代谢细胞因子之间存在反比关系，其可以表征为轻度炎症状态。

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 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 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 population based 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 (¿) of the joint. This results in permanent damage to articulating surfaces or failure of the joint to return to a low ¿ of 0.001. Aim 2: Blocking the Effects of TNF-¿ Through the Administration of a TNF-¿ Inhibitor Partially Restores the Lubricating Ability of Diarthrodial Joints Following ACL Injury. Hypothesis: TNF-¿ play a significant role in mediating changes in lubricin metabolism following ACL injury. Blocking the effects of TNF-¿ 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-¿. Hypothesis: An inverse relationship exists between lubricin concentration and catabolic cytokines in clinical aspirates which can be characterized as a mild inflammatory state.