Qualification of Prognostic and Diagnostic Biomarkers of Knee Osteoarthritis

摘要 骨关节炎(OA)的治愈方法仍然难以捉摸。这在很大程度上是由于两大障碍，即无法 在出现不可逆转的体征和顽固的症状之前，及早发现骨性关节炎，并且无法 根据传统使用的指标(年龄、性别、体重指数、 膝关节疼痛和关节间隙宽度)。后一个挑战是导致临床试验的低功率和 无数次药物试验失败。使用系统、不偏不倚和迭代的方法，我们创建了多个 反应监测(MRM)蛋白质组学小组用于基于血清的膝关节骨性关节炎结构进展和预测 膝骨性关节炎的诊断。蛋白质的选择是基于广泛的发现蛋白质组学研究的结果 在膝关节骨性关节炎放射学进展者和非进展者(3-4年)的滑液、尿液和血清中 后续行动)和对照。这项工作的最终目标是使这些新的生物标志物候选人在 较大的骨性关节炎表型良好的队列中膝关节骨关节炎进展和骨关节炎诊断的背景 该倡议、约翰斯顿县骨性关节炎项目和清福德队列。有了这个进一步的资格， 这些新的生物标志物工具将对其临床试验和临床使用的潜在效用具有非常重要的意义 告知OA患者的表型和早期识别和治疗的策略。我们还打算 寻求食品和药物管理局(FDA)对由此产生的最佳标记集的正式资格 促进将其用作药物开发工具的提案。

Abstract A cure for osteoarthritis (OA) remains elusive. This is due in large part to two major obstacles, inability to detect OA sufficiently early before the onset of irreversible signs and recalcitrant symptoms, and inability to identify individuals at high risk of progression based on traditionally used metrics (age, sex, body mass index, knee pain and joint space width). The latter challenge is responsible for low powering of clinical trials and numerous drug trial failures. Using a systematic, unbiased and iterative approach, we have created a multiple reaction monitoring (MRM) proteomic panel for serum-based prediction of knee OA structural progression and diagnosis of knee OA. The selection of proteins was based on results of extensive discovery proteomic studies in synovial fluid, urine, and serum from knee OA radiographic progressors and non-progressors (with 3-4 year follow-up) and controls. The ultimate goals of this work are to qualify these new biomarker candidates in the contexts of knee OA progression and OA diagnosis in larger well-phenotyped cohorts from the Osteoarthritis Initiative, the Johnston County Osteoarthritis Project and the Chingford cohorts. With this further qualification, these new biomarker tools will be very significant for their potential utility for clinical trial and clinical use to inform strategies for phenotyping and earlier identification and treatment of OA patients. We also intend to pursue formal Food and Drug Administration (FDA) qualification of the optimal marker set yielded by this proposal to facilitate their use as drug development tools.