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

骨关节炎（OA）是关节炎的最常见形式，并且是疼痛和残疾的主要原因，其中由于关节组织的持续侵蚀和重塑而存在关节功能的进行性丧失。目前没有针对疾病的改良治疗方法，患者依赖于简单的止痛药，最终进行关节置换手术。调查导致疾病的途径一直非常具有挑战性，因为人类的状况在其过程中非常多变，很难从患者身上获得组织（关节置换手术除外），我们目前没有办法检测早期疾病。OA的动物模型具有重要的实用性，因为疾病可以在病症的所有阶段进行研究，组织容易获得，并且疾病的发作是已知的。在过去的10年中，由于使用了由手术关节失稳诱导的OA小鼠模型，取得了许多进展。将这些模型与具有遗传修饰的小鼠相结合，揭示了对OA过程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调查。在开发新的治疗OA的进展是很可能出现在临床前model.Evaluation关节损伤的临床和动物模型的OA是由于无法成像软骨准确和非侵入性。X光片通过关节间隙的减少来测量软骨损失，因此只能发现相对晚期的疾病。在动物模型中，关节损伤通常在整个研究中定期处死动物（通常为4-12周）后通过组织学评估。后者根据所需的时间点数量增加了每项研究中使用的动物数量。一种非侵入性的成像方法，能够可视化关节软骨随着时间的推移而退化，这将大大减少关节炎研究中使用的动物数量。这样一个定量的系统也可能增加测量的可靠性，从而减少数量。我们已经证明了标记软骨特异性分子以特异性地可视化软骨是可能的。在这个项目中，我们将开发一种新的成像剂，可以与microCT扫描相结合，以创建一个敏感的，定量的软骨评估工具在OA。这最初将大大减少每个OA研究使用的动物数量，并可能转化为人类早期OA的临床成像剂。

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.