Tribosupplementation of Injured Joints

受伤关节的摩擦补充

• 批准号: 7670043
• 负责人: GREGORY D. JAY
• 金额: $ 20.72万
• 依托单位: TRIBOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670043
• 关键词: Acute; Adhesions; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Arthritis; Binding; Biocompatible Materials; Biological; Biological Preservation; Biological Process; Body mass index; Cartilage; Catabolism; Cathepsins B; Cells; Chondrocytes; Clinical; Collagen Type II; Contracts; Coupled; Data; Degenerative polyarthritis; Disease; Down-Regulation; Emergency Situation; Engineering; Etanercept; Failure; Fibroblasts; Film; Foreign-Body Reaction; Foundations; Friction; GAG Gene; Human; Immune response; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Intellectual Property; Joints; Knockout Mice; Knowledge; Laboratories; Lead; Left; Leukocyte Elastase; Link; Lubricants; Lubrication; Measures; Mechanics; Mediating; Medical; Modeling; Morbidity - disease rate; Occupations; Pathogenesis; Patients; Peptide Hydrolases; Physicians; Play; Polymers; Population Study; Positioning Attribute; Process; Protein Binding; Proteins; Proteolysis; Rattus; Recombinants; Rheumatoid Arthritis; Risk; Risk Factors; Role; Supplementation; Surface; Synovial Fluid; TNF gene; Techniques; Technology; Testing; Toxic effect; Tumor Necrosis Factor-alpha; Work; anterior cruciate ligament rupture; articular cartilage; cost; cytokine; human TNF protein; hyaluronate; in vivo; inhibitor/antagonist; injured; joint injury; lubricin; nano; prevent; public health relevance; restoration

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.

描述（由申请人提供）：受伤是骨关节炎（OA）的良好危险因素，这是几项大型纵向人群研究所支持的。半月板和ACL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剂介导的，该润滑剂形成有序的纳米膜，并通过空间排斥提供抗粘附。最近的观察结果表明，ACL损伤患者中润滑剂既下调和分解代谢。该观察结果以及润滑剂无效小鼠的快速关节表面破坏表明，保留润滑剂或恢复可能在减轻损害创伤性关节损伤的人类退行性关节疾病的风险方面起着重要作用。通过将润滑剂重新铺面通过将润滑剂引入创伤的大鼠关节，已显示通过每周使用润滑剂注射润滑剂来减慢这种进展。此外，拮抗TNF-Alpha是一种下调润滑剂的炎性细胞因子，已证明具有依那耐酸的脂肪因子可以在大鼠ACL模型中重新建立软骨表面的润滑剂。重组润滑剂的使用用于创伤的滑膜的软骨保护可能具有显着的商业价值。我们提出了2个互连特定的目的，可以使建立良好的大鼠ACL横断模型确定托工是否会减慢创伤后OA的进展。在AIM 1中，我们将确定每周添加人润滑剂是否会减少通过表面粗糙，II型胶原型降解，GAG损失和QPCR降解标记物测量的软骨损失。我们还将确定透明质酸盐的共同给药是否比单独的润滑剂更有效。在AIM 2中，我们将确定是否通过依那耐酸的共同给药阻止TNF-Alpha的影响，从而增强了AIM 1在AIM 1中通过防止重新引入的润滑剂的下游蛋白水解所实现的软骨保护。这些目标在急性关节损伤的管理中既转化又具有临床意义。初步数据表明，托工是可以实现的，并且是针对软骨轴承的纳米脱水基础，其特征在于摩擦非常低。商业价值很高，因为这项技术将增强使用透明质酸盐的粘附剂量的广泛实践。 PI非常适合这些研究，因为他为我们目前对润滑剂的了解，与磨损外观相关的软骨摩擦做出了重要贡献，并且是一名实践急诊医师。 PI已经与分包合同的CO-I合作，他确定ACL损伤患者的润滑剂水平降低。 公共卫生相关性：用润滑剂的哺乳动物关节可以恢复软骨的保护并防止其损坏。诸如ACL破裂之类的受伤后的这种做法可能在保护关节免受发展退行性关节疾病的情况下至关重要。这项动物研究将表明，将润滑剂注入关节可以防止关节变性。