Development of novel imaging agents for the prospective quantification of joint damage to reduce animal numbers in osteoarthritis research

骨关节炎（OA）是最常见的关节炎形式，也是导致疼痛和残疾的主要原因，由于关节组织的持续侵蚀和重塑，关节功能逐渐丧失。目前还没有改良的治疗方法，患者依赖于简单的止痛药和最终的关节置换手术。研究导致疾病的途径是非常具有挑战性的，因为人类的状况在其过程中是非常多变的，很难从患者身上获得组织（除了关节置换手术），而且我们目前没有办法检测早期疾病。骨性关节炎的动物模型具有重要的实用性，因为疾病可以在疾病的所有阶段进行研究，组织很容易获得，并且疾病的发病是已知的。在过去的10年里，由于手术关节失稳引起的OA小鼠模型的使用，已经取得了一些进展。将这些模型与基因修饰的小鼠相结合，揭示了OA过程中重要的几个关键途径/分子。许多学术和制药公司使用这些模型进行此类研究。开发OA新疗法的进展很可能来自临床前模型。由于无法对软骨进行准确和无创成像，临床上和动物模型中对关节损伤的评估都受到了阻碍。x光片通过关节间隙的缩小来测量软骨的损失，因此只能发现相对晚期的疾病。在动物模型中，在整个研究期间（通常为4-12周）定期牺牲动物后，通常通过组织学评估关节损伤。后者增加了每项研究中使用的动物数量所需的时间点数量。一种能够观察关节软骨随时间退化的非侵入性成像方法将大大减少用于关节炎研究的动物数量。这样一个定量的系统也可能增加测量的可靠性，从而减少数字。我们已经证明，有可能标记软骨特定分子，以使软骨特异性可视化。在本项目中，我们将开发一种新型显像剂，可与微ct扫描相结合，以创建OA中敏感、定量的软骨评估工具。这将在最初显著减少每个OA研究使用的动物数量，并有可能转化为人类早期OA的临床显像剂。

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability, where there is progressive loss of joint function due to continual erosion and remodelling of the tissues of the joint. There are currently no modifying treatments for disease and patients rely on simple pain killers and ultimately joint replacement surgery. Investigating the pathways that cause disease has been very challenging as the human condition is very variable in its course, it is difficult to obtain tissues from patients (except at joint replacement surgery) and we currently have no ways of detecting early disease. Animal models of OA have significant utility because disease can be studied at all stages of the condition, tissues are readily available, and the onset of disease is known. In the past 10 years a number of advances have arisen from the use of mouse models of OA induced by surgical joint destabilisation. Combining these models with mice that have genetic modification has revealed several key pathways/molecules important for the OA process. Many academic and pharmaceutical companies use these models for such investigations. Progress in developing novel treatments for OA is very likely to arise from pre-clinical models.Evaluation of joint damage both in the clinic and in animal models of OA is hampered by the inability to image cartilage accurately and non-invasively. X-ray radiographs measure cartilage loss by a reduction in the joint space, thus are only able to pick up relatively advanced disease. In animal models, joint damage is typically assessed by histology after sacrificing the animals at regular intervals throughout studies (usually 4-12 weeks). The latter increases the number of animals used in each study by the number of time points required. A non-invasive imaging method that would be able to visualise the degradation of the articular cartilage over time would greatly reduce the numbers of animals being used in arthritis research. Such a system, being quantitative, might also increase the reliability of measurements and thus also reduce numbers. We have already demonstrated that it is possible to tag cartilage specific molecules to visualise the cartilage specifically. In this project, we will develop a novel imaging agent that can be combined with microCT scanning to create a sensitive, quantitative cartilage assessment tool in OA. This will initially dramatically reduce the number of animals used per OA study and is potentially translatable into a clinical imaging agent for early OA in humans.