Agrin, a unique growth factor for cartilage regeneration in osteoarthritis

关节软骨是覆盖在长骨末端的组织，它允许关节无摩擦运动。关节软骨的丧失是骨关节炎的主要特征，它会导致关节疼痛，无法行走或执行简单的任务。在英国，骨关节炎是导致残疾津贴的主要原因，并与巨大的间接费用相关。60岁以上的人口中有超过三分之一患有此病，因此它是影响幸福感的主要因素之一，尤其是老年人。到目前为止，我们还没有任何治疗方法可以阻止骨关节炎的发展。现有的治疗方法仅限于止痛药和关节置换。虽然关节置换术通常是有效的，但有五分之一的患者不能达到患者的期望，并且患者的寿命有限，通常需要进行复杂且具有挑战性的翻修手术。由于人们的寿命越来越长，越来越多的人在更早的时候患上骨关节炎，关节置换术的严重局限性变得越来越突出。我们发现软骨细胞产生的一种叫做Agrin的分子对软骨的健康至关重要。在骨关节炎中，这种分子被降解，然而我们知道，给予Agrin将有助于形成新的软骨，也将限制软骨降解分子的产生，如MMP-3。最后，我们发现Agrin起作用的一种方式是关闭一种叫做WNT的分子信号，这种分子信号被证明有利于软骨破裂，当过度活跃时，容易使人患上骨关节炎。在这项研究中，我们打算测试是否确实将Agrin直接注入关节可以治疗骨关节炎。首先，我们将对老鼠进行基因工程改造，这样当我们给老鼠注射一种特殊的药物时，它就会在老鼠的软骨内产生Agrin。这将确保agin在软骨内被最佳地传递，并且我们看到的任何效果都是由于agin对软骨的影响。我们将通过破坏膝关节的半月板来诱导这些小鼠的骨关节炎，从而导致机械关节不稳定。半月板损伤也是人类骨关节炎发展的常见原因。一旦老鼠患上骨关节炎，我们将给它们注射一种特殊的药物，这种药物将诱导软骨产生Agrin。然后我们将看到，与对照组相比，软骨中的Agrin诱导是否会导致骨关节炎的愈合。除了这种仅在软骨中增加Agrin产生的遗传方法外，我们还将使用诱导Agrin产生的病毒，或在炎症组织中不能降解的较小片段的Agrin。这些病毒将被注射到关节中，就像人工合成的Agrin会被注射到病人体内一样。因此，Agrin不仅会进入软骨，还会进入其他关节组织，如骨头和称为滑膜的关节内层。这将使我们能够看到Agrin给药对关节所有组织的影响。最后，利用分子方法，我们将研究Agrin激活软骨细胞的机制。这一目标的实现将使我们能够识别已经存在的化合物，这些化合物可以激活相同的受体和相同途径的细胞成分，并可能使我们不必合成Agrin就能达到相同的效果。

The articular cartilage is the tissue that covers the ends of the long bones and that allows the frictionless motion of the joint. The loss of the articular cartilage, which is the main feature of osteoarthritis, leads to joint pain and incapacity to walk or perform simple tasks. Osteoarthritis is the leading cause for disability allowance in UK and is associated with huge indirect costs. It affects over 1/3 of the population over the age of 60 and therefore is one of the major factors affecting well-being particularly in the elderly. To-date, we do not have any treatment that stops progression of osteoarthritis. Available treatments are limited to pain killers and joint replacement. Although generally effective, joint replacement does not live up to the patients' expectations in up to one in five patients, and has a limited life span often requiring complex and challenging revision surgery. This serious limitation of joint replacement is becoming more prominent due to the fact that people live much longer and because more people are developing osteoarthritis at an earlier age. We have discovered that a molecule called Agrin, produced by cartilage cells, is essential for cartilage health. In osteoarthritis this molecule is degraded, however we know that administering Agrin will help forming new cartilage and will also limit the production of cartilage-degrading molecules such as MMP-3. Finally, we have discovered that one way that Agrin works is by shutting down a molecular signal called WNT which has been shown to favour cartilage breakdown and, when excessively active, predisposes people to develop osteoarthritis.In this study we intend to test if indeed administering Agrin directly into the joint can treat osteoarthritis. First, we will genetically engineer mice so that Agrin is produced within cartilage when we administer a special drug. This will ensure that Agrin is delivered optimally within the cartilage and that whatever effect we see is due to the effect of Agrin on cartilage. We will induce osteoarthritis in these mice by damaging the meniscus in the knee, which results in mechanical joint instability. Damage to the meniscus is a common cause of osteoarthritis development also in people. Once the mice have developed osteoarthritis we will administer the special drug that will induce Agrin production in the cartilage. We will then see if, compared to controls, Agrin induction in cartilage leads to healing of osteoarthritis.In addition to this genetic approach which leads to increased Agrin production only in cartilage, we will use also viruses that induce the production of Agrin, or smaller fragments of Agrin that cannot be degraded in inflamed tissues. These viruses will be injected into the joint just like synthetic Agrin would be in patients. Therefore Agrin will go not only into cartilage, but also into other joint tissues such as the bone and the internal lining of the joint called synovial membrane. This will enable to see the effects of Agrin administration to all tissues of the joint.Finally, using molecular approaches, we will study the mechanism by which Agrin activates cartilage cells. The delivery of this aim will enable us to identify already existing compounds that can activate the same receptor and cellular components of the same pathway and may enable us to achieve the same effects without having to make synthetic Agrin.