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，这是几项大型纵向人群研究支持的。半月板和前交叉韧带损伤的患者尤其有早期骨性关节炎的风险。关节表面的软骨保护是由润滑剂介导的，润滑剂形成有序的纳米膜，并通过空间斥力提供抗粘连。最近的观察表明，在前交叉韧带损伤的患者中，润滑剂的表达下调和分解代谢。这一观察结果，再加上空白小鼠关节表面的快速破裂，表明保存润滑剂或修复润滑剂可能在降低患有创伤性关节损伤的人类退行性关节疾病的风险方面发挥重要作用。通过将润滑剂重新注入创伤大鼠关节中重新铺设关节表面，已被证明通过每周注射润滑剂在损伤周期间减缓了这一进展。此外，用依那西普拮抗肿瘤坏死因子-α，一种下调润滑素的炎性细胞因子，已被证明在大鼠前交叉韧带模型的软骨表层重新建立了润滑素的存在。使用重组润滑剂对损伤的滑膜关节进行软骨保护可能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，利用已建立的大鼠前交叉韧带横断模型来确定三种补充是否减缓了创伤后骨性关节炎的进展。在目标1中，我们将通过表面粗化、II型胶原降解、GAG丢失和降解标记物的定量聚合酶链式反应来确定每周添加人类润滑剂是否能减少软骨丢失。我们还将确定联合使用透明质酸是否比单独使用润滑剂更有效。在目标2中，我们将确定是否通过联合应用依那西普来阻断肿瘤坏死因子-α的作用，从而通过阻止重新引入的润滑剂的下游蛋白分解来增强在目标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转化性和临床意义。初步数据表明，摩擦补充是可以实现的，并且是针对软骨轴承的纳米摩擦学基础，其特点是摩擦力非常低。商业价值很高，因为这项技术将加强广泛存在的用透明质酸盐补充粘性物质的做法。PI非常适合于这些研究，因为他对我们目前关于润滑剂的知识做出了重大贡献，他是一名执业急诊医生，与软骨摩擦和磨损的外观有关。PI已经与分包商Co-I合作，后者已经确定前交叉韧带损伤患者的润滑剂水平降低。公共卫生相关性：用润滑剂对哺乳动物关节进行摩擦补充可以恢复对软骨的保护并防止其损坏。损伤后的这种做法，如前交叉韧带断裂，可能在保护关节免受退行性关节疾病的影响方面起着关键作用。这项动物研究将表明，向关节内注入润滑剂可以防止关节退变。

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.