Tribosupplementation of Injured Joints

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，得到了几项大型纵向人群研究的支持。特别是半月板和前交叉韧带损伤的患者有早期OA的风险。关节表面的软骨保护是由润滑素介导的，润滑素形成有序的纳米膜，并通过位阻排斥提供抗粘附。最近的观察表明，前交叉韧带损伤患者的润滑素下调和分解代谢。这一观察结果与润滑油缺失小鼠关节表面的快速破坏相结合，表明保留润滑剂或其修复可能在减轻创伤性关节损伤患者退行性关节疾病的风险方面发挥重要作用。通过将润滑油重新引入创伤大鼠关节的关节表面重新铺设，已经证明通过每周注射润滑油可以减缓损伤期的这种进展。此外，在大鼠ACL模型中，用依那西普拮抗tnf - α（一种下调润滑素的炎症细胞因子）已被证明可以重建软骨浅表区润滑素的存在。应用重组润滑素对创伤性滑膜关节的软骨保护具有重要的商业价值。我们提出了两个相互关联的特定目标，涉及一个完善的大鼠ACL横断模型，以确定摩擦补充是否减缓创伤后OA的进展。在目的1中，我们将通过表面粗化、II型胶原降解、GAG损失和降解标记物的QPCR来测定每周添加人体润滑油是否会减少软骨损失。我们还将确定是否联合使用透明质酸比单独使用润滑素更有效。在Aim 2中，我们将确定通过联合使用依那西普来阻断tnf - α的作用是否能通过阻止重新引入的润滑素的下游蛋白水解来增强Aim 1中实现的软骨保护。这些目标在急性关节损伤的治疗中具有翻译和临床意义。初步数据表明，摩擦补充是可以实现的，并且针对软骨轴承的纳米摩擦学基础，其特点是非常低的摩擦。该技术的商业价值很高，因为它将扩大透明质酸粘补的广泛实践。PI非常适合这些研究，因为他对我们目前的润滑知识做出了重大贡献，将软骨摩擦与磨损的外观联系起来，并且是一名执业急诊医生。PI已经与分包公司Co-I合作，后者已经确定前交叉韧带损伤患者的润滑素水平降低。公共卫生相关性：在哺乳动物关节中添加润滑素可以恢复对软骨的保护并防止其损伤。这种做法在受伤后，如前交叉韧带破裂，可能是保护关节免受退行性关节疾病发展的关键。这项动物研究将表明，向关节注射润滑油可以防止关节变性。

DESCRIPTION (provided by applicant): Injury is a well established risk factor in the pathogenesis of osteoarthritis (OA) as supported by several large longitudinal population studies. Patients with meniscal and ACL injuries in particular are at risk for early OA. Chondroprotection of the joint surface is mediated by lubricin which forms an ordered nanofilm and provides anti-adhesion via steric repulsion. Recent observations indicate that lubricin is both downregulated and catabolized in patients with ACL injuries. This observation coupled with the rapid joint surface disruption in lubricin null mice suggest that preserving the lubricant or its restoration could play a major role in mitigating the risk of degenerative joint disease in humans with traumatic joint injuries. Resurfacing of the articular surface by re- introducing lubricin into a traumatized rat joint has been shown to slow this progress in the peri-injury period by using weekly injections of lubricin. In addition, antagonizing TNF-alpha, an inflammatory cytokine that downregulates lubricin, with etanercept has been shown to re-establish the presence of lubricin in the superficial zone of cartilage in a rat ACL model. The use of recombinant lubricin for the chondroprotection of the traumatized synovial joint could have significant commercial value. We propose 2 interconnecting specific aims engaging a well established rat ACL transection model to determine if tribosupplementation slows the progression of post-traumatic OA. In Aim 1 we will determine if the weekly addition of human lubricin reduces cartilage loss as measured by surface roughening, collagen type II degradation, GAG loss and QPCR for degradative markers. We will also determine if the co-administration of hyaluronate is more efficacious than lubricin alone. In Aim 2 we will determine if blocking the effects of TNF-alpha through the co-administration of etanercept enhances the chondroprotection achieved in Aim 1 by preventing the downstream proteolysis of the re-introduced lubricin. These aims are both translational and clinically meaningful in the management of acute joint injuries. Preliminary data indicate that tribosupplementation is achievable and is directed at the nanotribological foundation of the cartilage bearing which is characterized by very low friction. The commercial value is high as this technology would augment the widespread practice of viscosupplementation with hyaluronates. The PI is well suited for these studies as he has significantly contributed to our current knowledge of lubricin, associated cartilage friction with the appearance of wear, and is a practicing emergency physician. The PI already collaborates with the sub-contract Co-I who has established that lubricin levels are decreased in patients with ACL injuries. PUBLIC HEALTH RELEVANCE: Tribosupplementing mammalian joints with lubricin can restore the protection of cartilage and prevent its damage. This practice following an injury, such as an ACL rupture, may be pivotal in protecting a joint from developing degenerative joint disease. This animal study will show that injecting lubricin into a joint can prevent joint degeneration.