Tribosupplementation of Injured Joints

受伤关节的摩擦补充

• 批准号: 8455361
• 负责人: GREGORY D. JAY
• 金额: $ 33.83万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455361
• 关键词: Address; Adhesions; Animal Model; Animals; Anterior Cruciate Ligament; Apoptosis; Arthritis; Binding; Biological Preservation; Biomechanics; Bovine Cartilage; Cartilage; Chondrocytes; Clinical Trials; Collagen Type II; Contracts; Coupled; Data; Degenerative polyarthritis; Dose; Effectiveness; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Family suidae; Fluorescent in Situ Hybridization; Foundations; Friction; GAG Gene; Glycoproteins; Gold; Histology; Human; In Vitro; Inflammatory Response; Injectable; Injection of therapeutic agent; Injury; Interleukin-1; Intra-Articular Injections; Joints; Knee; Knockout Mice; Knowledge; Lateral; Lubricants; Lubrication; Measures; Mechanics; Medial; Mediating; Modeling; Operative Surgical Procedures; Outcome Measure; Pathogenesis; Patients; Phase; Physicians; Placebo Control; Placebos; Play; Pre-Clinical Model; Proteins; Proteoglycan; Rattus; Recombinants; Reporting; Research; Risk; Risk Factors; Role; Saline; Simulate; Structure; Supplementation; Surface; Surgical Injuries; Synovial Fluid; System; Technology; Testing; Time; articular cartilage; base; cartilage metabolism; cytokine; experience; high risk; hyaluronate; improved; in vivo; injured; joint injury; lubricin; novel therapeutics; osteochondral tissue; phase 1 study; prevent; public health relevance; response; secondary outcome; standard care; technology development

DESCRIPTION (provided by applicant): Joint injury is a well established risk factor in the pathogenesis of post-traumatic osteoarthritis (PTOA). In particular, patients with meniscal tears are at high risk for early PTOA. Chondroprotection of the joint surface is mediated by lubricin, a large glycoprotien which forms a lubricating nanofilm on the cartilage surface and provides anti-adhesion via steric repulsion. Recent observations indicate that lubricin is both downregulated and catabolized in patients following traumatic joint injuries. This observation, coupled with the rapid joint surface disruption in lubricin null mice, suggest that preserving or restoring the lubricant could play a major role in mitigating the risk of degenerative joint disease in patients with meniscal injuries, either before or after partial meniscectomy. Our Phase 1 studies clearly show that re-introducing lubricin into the anterior cruciate ligament injured rat joint ("tribosupplementation") slowed PTOA pathogenesis in the peri-injury period following either weekly intra-articular injections or a single dose, escalated injection of recombinant human lubricin. The use of recombinant lubricin for the chondroprotection of the traumatized synovial joint thus could have significant commercial value as a new therapeutic treatment. In Phase II, we propose three interconnecting specific aims based on our well established pre-clinical model of joint injury to determine if tribosupplementation slows the progression of PTOA following partial meniscectomy. In Aim 1, we will determine if the co-administration with hyaluronate is more efficacious than recombinant human lubricin alone in enhancing the chondroprotection in a porcine cartilage bearing. In Aim 2, we will determine if this potentiating effect results in a greater reduction in chondrocyte apoptosis, especially in the presence of cartilage which has been degraded by IL-1. In Aim 3, we will determine if recombinant human lubricin reduces cartilage loss following partial medial meniscectomy, in vivo, as measured by histology, collagen type II degradation, GAG loss and qPCR for degradative markers. These aims are translational and will provide the foundation for a clinical trial. Our preliminary data indicate that tribosupplementation is achievable and is directed at the nanotribological foundation of the cartilage bearing, which is characterized by very low cartilage friction. The commercial value is high as this technology could improve the widespread practice of viscosupplementation with hyaluronate. The PI and his research team are well suited to perform these studies in that they have significantly contributed to the current knowledge of lubricin and its association with cartilage friction, cartilage wear, and chondrocyte apoptosis. The PI is also a practicing emergency physician and already collaborates with the sub-contract Co-I, who has also performed several large animal studies to date.

描述（由申请人提供）：关节损伤是创伤后骨关节炎（PTOA）发病机制中公认的危险因素。特别是半月板撕裂的患者发生早期 PTOA 的风险较高。关节表面的软骨保护是由润滑素介导的，润滑素是一种大的糖蛋白，它在软骨表面形成润滑纳米膜，并通过空间排斥提供抗粘连。最近的观察表明，在创伤性关节损伤后的患者中，润滑素的表达下调和分解代谢。这一观察结果，加上润滑素无效小鼠的关节表面快速破坏，表明在部分半月板切除术之前或之后，保留或恢复润滑剂可以在减轻半月板损伤患者退行性关节疾病的风险方面发挥重要作用。我们的一期研究清楚地表明，在每周关节内注射或单剂量、递增注射重组人lubricin后，将lubricin重新引入前十字韧带损伤的大鼠关节（“摩擦补充”）可减缓损伤周围期的PTOA发病机制。因此，使用重组润滑素来保护受伤滑膜关节的软骨，作为一种新的治疗方法可能具有显着的商业价值。在第二阶段，我们根据我们完善的临床前关节损伤模型提出了三个相互关联的具体目标，以确定摩擦补充是否能减缓部分半月板切除术后 PTOA 的进展。在目标 1 中，我们将确定与透明质酸盐共同给药是否比单独使用重组人润滑素更有效地增强猪软骨轴承的软骨保护。在目标 2 中，我们将确定这种增强作用是否会导致软骨细胞凋亡的更大程度减少，特别是在存在已被 IL-1 降解的软骨的情况下。在目标 3 中，我们将通过组织学、II 型胶原蛋白降解、GAG 损失和降解标记物的 qPCR 测量，确定重组人润滑素是否能减少体内部分内侧半月板切除术后的软骨损失。这些目标是转化性的，将为临床试验奠定基础。我们的初步数据表明，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，其特点是软骨摩擦力非常低。商业价值很高，因为该技术可以改善透明质酸补充粘稠剂的广泛实践。 PI 和他的研究团队非常适合进行这些研究，因为他们对当前有关润滑素及其与软骨摩擦、软骨磨损和软骨细胞凋亡的关系的认识做出了重大贡献。该 PI 也是一名执业急诊医师，并且已经与分包 Co-I 合作，该分包 Co-I 迄今为止还进行了多项大型动物研究。