Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia. christopher.little@ sydney.edu.au
Nat Rev Rheumatol. 2013 Aug;9(8):485-97. doi: 10.1038/nrrheum.2013.72. Epub 2013 May 21.
Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA.
骨关节炎（OA）是最常见的关节疾病，是导致残疾的主要原因，在全球范围内造成了巨大（且不断增长）的社会经济成本。尽管 OA 的重要性日益凸显，但将疾病修饰型 OA 疗法从实验室转化为临床实践的进展缓慢。这是因为临床前研究中使用的 OA 模型与人类临床试验中评估的疾病之间存在差异。大多数 OA 动物模型通过对年轻个体关节生物力学的手术或机械破坏来诱导疾病，而不是模拟与年龄相关的自发性疾病的发展。这种由不稳定引起的动物关节疾病最能模拟人类在创伤性事件后发生的关节炎，即创伤后 OA（PTOA）。基因修饰小鼠的研究表明，与自发性 OA 相比，PTOA 具有明显不同的分子病理生理学，这可能解释了从临床前 OA 治疗试验到临床 OA 治疗试验的翻译效果不佳。本文综述了基因修饰小鼠研究中得出的关于 PTOA 预防和修饰的潜在分子靶点的最新数据，并描述了它们在临床前治疗试验中的验证情况。本文重点讨论了如何将这些发现最好地转化为人类，并确定了成功实施 PTOA 疾病修饰药物临床试验的潜在挑战。
