Function of CXCR2 signalling within the articular cartilage

软骨是覆盖在我们长骨末端的组织，使我们的关节能够无摩擦地运动。这种组织在骨关节炎期间丢失（退化），导致关节疼痛和无法行走或执行简单任务。在英国，骨关节炎是领取伤残津贴的主要原因；在50岁以上的人口中，有超过三分之一的人受其影响，因此是影响幸福感的一个主要因素，尤其是老年人。到目前为止，我们没有任何治疗方法可以阻止骨关节炎的发展，唯一的补救措施是止痛药和关节置换术。虽然关节置换术通常有效，但约20%的病例不能达到患者的期望，并且寿命有限，通常需要复杂且具有挑战性的翻修手术（成功率很低）。由于人们寿命的延长，以及越来越多的人在年轻时患上骨关节炎（例如，由于肥胖或运动损伤），关节置换术的这些严重局限性正变得越来越突出。损伤后，软骨会做出反应以维持其完整性，然而，当这种反应不足时，软骨会发生损伤。令人兴奋的是，最近的数据表明，在动物模型中，支持这些内在的保护反应是非常成功的，可以防止软骨破裂，甚至再生受损组织。我们发现一种叫做ELR+CXC趋化因子的分子参与了这些保护性反应。以前我们知道这些分子可以吸引免疫细胞到炎症部位，我们发现，当存在于健康软骨中时，这些分子在损伤后支持软骨完整性方面具有完全不同的作用。因此，缺乏这种保护性反应的小鼠更容易患实验性骨关节炎。我们发现ELR+CXC趋化因子保留在软骨组织中，因为它们与称为HSPGs的复杂糖分子结合。因此，软骨中存在的ELR+CXC趋化因子不能吸引炎症细胞，而是帮助软骨保持健康并从轻微损伤中恢复。在骨关节炎期间，当软骨受到严重损伤时，ELR+CXC趋化因子从组织中丢失，因此它们不再能够保护软骨，并且它们也可能直接导致炎症。在这项研究中，我们打算回答以下问题：1)这些趋化因子究竟是如何在骨关节炎期间保护软骨的？为了做到这一点，我们将制作一个小鼠模型，使我们能够将趋化因子对软骨的影响与对关节功能和炎症的其他方面的影响分开。重要的是，它还将提供在骨关节炎发展过程中这些分子起作用的信息，如果我们要利用这种保护活性用于治疗应用，这是必不可少的。2)支持软骨健康最有效的ELR+CXC趋化因子是什么？有不同的ELR+CXC趋化因子，有数据表明，一些可能比其他更好地支持软骨完整性。确定最佳趋化因子对于治疗应用非常重要。3)我们是否可以修改趋化因子，使它们不能吸引炎症细胞，但仍保留其保护软骨的能力？我们将通过改变它们与HSPGs结合的方式来实现这一目标，这样它们就不能附着在血管上，从而招募炎症细胞。4)我们将构建含有并保留ELR+CXC趋化因子的生物材料，测试组织工程在不引起炎症的情况下修复/保护软骨的潜力。该项目源于我们发现趋化因子的这种意想不到的功能，并确定了一种保护/修复骨关节炎软骨的方法：骨关节炎是导致残疾的主要原因，我们仍然无法治愈。

Cartilage is the tissue that covers the ends of our long bones, allowing the frictionless motion of our joints. This tissue is lost (degraded) during osteoarthritis, leading to joint pain and incapacity to walk or perform simple tasks. Osteoarthritis is the leading cause for disability allowance in the UK; it affects greater than 1 in 3 of the population over the age of 50 and therefore is a major factor affecting well-being, particularly in the elderly. To-date, we do not have any treatment that stops progression of osteoarthritis and the only remedies are pain killers and joint replacement. Although generally effective, joint replacement does not live up to patients' expectations in ~20% of cases, and has a limited life span often requiring complex and challenging revision surgery (with a poor success rate). These serious limitations of joint replacement are becoming more prominent due to the fact that people live much longer and because more people are developing osteoarthritis at a younger age (e.g. due to obesity, or following sports injuries). Following injury, cartilage responds to maintain its integrity, however, cartilage breakdown progresses when this response is insufficient. Excitingly, recent data have shown that supporting these intrinsic protective responses can be very successful in animal models, preventing cartilage breakdown and even regenerating damaged tissue. We have discovered that molecules called ELR+CXC chemokines are involved in these protective responses. Previously known for attracting immune cells to sites of inflammation, we have discovered that, when present within healthy cartilage, these molecules have a totally different role supporting cartilage integrity following injury. As a consequence, mice that have been engineered to lack this protective response are more susceptible to experimental osteoarthritis. We discovered that ELR+CXC chemokines are retained in the cartilage tissue because they are bound to complex sugar molecules called HSPGs. Therefore, ELR+CXC chemokines present in cartilage cannot attract inflammatory cells and, instead, help cartilage to stay healthy and recover from minor injury. When, during osteoarthritis, cartilage becomes badly damaged, ELR+CXC chemokines are lost from the tissue so that they can no longer protect cartilage and they may also contribute directly to inflammation.In this study we intend to answer the following questions: 1) How exactly do these chemokines protect cartilage during osteoarthritis? To do this we will make a mouse model that will enable us to separate the effects of chemokines on cartilage from those on other aspects of joint function and inflammation. Importantly, it will also provide information on which point during the development of osteoarthritis these molecules function, which is essential if we are to harness this protective activity for therapeutic applications.2) What is the most potent ELR+CXC chemokine to support cartilage health? There are different ELR+CXC chemokines and there is data to suggest that some may be better than others at supporting cartilage integrity. Identifying the best chemokine is very important for therapeutic applications.3) Can we modify chemokines so that they become unable of attracting inflammatory cells and yet retain their capacity to protect cartilage? We will achieve this by modifying the way they bind to HSPGs so that they cannot adhere to blood vessels where they would recruit inflammatory cells.4) We will build a biomaterial containing and retaining ELR+CXC chemokines to test the potential of tissue engineering to repair/protect cartilage without causing inflammation.This project develops from our discovery of this unexpected function of chemokines and identifies a way we can protect/repair cartilage in osteoarthritis: a leading cause of disability for which we still do not have a cure.