Tribosupplementation of Injured Joints

描述(由申请人提供)：关节损伤是创伤后骨关节炎(PTOA)发病机制中一个公认的危险因素。尤其是半月板撕裂的患者，早期PTOA的风险很高。关节表面的软骨保护是由润滑素介导的，这是一种大的糖蛋白，它在软骨表面形成一层润滑纳米膜，并通过空间斥力提供抗粘连。最近的观察表明，在创伤关节损伤后的患者中，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润滑剂的快速破裂，表明在半月板部分切除之前或之后，保留或恢复润滑剂可能在降低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。我们的第一阶段研究清楚地表明，在每周关节内注射或单次递增注射重组人润滑剂后，在前十字韧带损伤的大鼠关节中重新引入润滑剂(“三次补充”)可以减缓损伤周围时期的PTOA的发病。因此，使用重组润滑剂对损伤的滑膜关节进行软骨保护作为一种新的治疗方法具有重要的商业价值。在第二阶段，基于我们已建立的关节损伤的临床前模型，我们提出了三个相互关联的特定目标，以确定三联补充剂是否减缓了半月板部分切除后PTOA的进展。在目标1中，我们将确定与透明质酸联合给药是否比单独使用重组人润滑剂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的减少，特别是在存在被IL-1降解的软骨的情况下。在目标3中，我们将在体内通过组织学、II型胶原降解、GAG丢失和降解性标志物的定量聚合酶链式反应(QPCR)来确定重组人润滑剂是否能够减少内侧半月板部分切除后的软骨丢失。这些目标是翻译的，将为临床试验提供基础。我们的初步数据表明，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的，其特征是软骨摩擦非常低。商业价值很高，因为这项技术可以改进广泛存在的用透明质酸盐粘性补充的做法。PI和他的研究团队非常适合进行这些研究，因为他们对当前关于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知识做出了重大贡献。PI也是一名执业急诊医生，已经与分包合同Co-I合作，Co-I到目前为止还进行了几项大型动物研究。

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.