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）：损伤是骨关节炎（OA）发病机制中一个公认的风险因素，这得到了几项大型纵向人群研究的支持。特别是踝关节和ACL损伤的患者有早期OA的风险。关节表面的软骨保护由润滑素介导，润滑素形成有序的纳米膜并通过空间排斥提供抗粘连。最近的观察表明，润滑素在ACL损伤患者中下调和分解代谢。这一观察结果与润滑素缺失小鼠中的快速关节表面破坏相结合，表明保存润滑剂或其修复物在减轻患有创伤性关节损伤的人类中退行性关节疾病的风险方面可以发挥重要作用。通过将润滑素重新引入到创伤大鼠关节中来进行关节表面的表面置换已经显示出通过使用每周注射润滑素来减缓损伤周围期的这种进展。此外，已经显示用依那西普拮抗TNF-α（一种下调润滑素的炎性细胞因子）在大鼠ACL模型中重新建立软骨浅表区中润滑素的存在。重组润滑素用于创伤性滑膜关节的软骨保护可能具有显著的商业价值。我们提出了2个相互关联的具体目标，采用一个完善的大鼠ACL横断模型，以确定摩擦补充剂是否减缓创伤后OA的进展。在目标1中，我们将确定每周添加人润滑素是否减少软骨损失，如通过表面粗糙化、II型胶原降解、GAG损失和降解标志物的QPCR所测量的。我们还将确定联合使用透明质酸是否比单独使用润滑素更有效。在目标2中，我们将确定通过依那西普联合给药阻断TNF-α的作用是否通过阻止重新引入的润滑素的下游蛋白水解来增强目标1中实现的软骨保护。这些目标在急性关节损伤的管理中具有转化和临床意义。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，其特征在于非常低的摩擦。商业价值很高，因为该技术将扩大透明质酸盐粘性补充的广泛实践。PI非常适合这些研究，因为他对我们目前对润滑素的了解做出了重大贡献，与磨损外观相关的软骨摩擦，并且是执业急诊医生。PI已经与分包商Co-I合作，Co-I已经确定ACL损伤患者的润滑素水平降低。 与公众健康的关系：摩擦补充哺乳动物关节润滑素可以恢复软骨的保护，防止其损坏。这种做法后受伤，如ACL断裂，可能是关键的保护关节发展退行性关节疾病。这项动物研究将表明，将润滑素注射到关节中可以防止关节退化。