Modulation of inflammatory processes as treatment strategy in osteoarthritis

骨关节炎（OA）是迄今为止最常见的关节疾病。目前没有阻止OA发作或进展的疗法。随着人口老龄化，OA对个人和社会经济的影响正在持续增长。为OA寻找有效的疾病缓解疗法是国际医学研究的重点。虽然OA以前被认为是一种由“磨损”定义的关节病，但有越来越多的证据表明细胞和分子途径正在驱动疾病的发作和进展。炎症与早期OA膝关节软骨丢失快速进展的风险显著增加相关，而在无既存OA的膝关节中，30个月随访期间软骨丢失的几率增加3倍。炎症不是副产品，但实际上可能在启动OA过程及其进展中发挥关键作用。OA中的特定炎症事件、其随时间的变化以及与“非OA诱导”炎症的差异尚未完全阐明。该提案旨在确定OA滑膜炎症过程的哪些组分是关键的，从而确定治疗该疾病的新药物靶点。确定炎症的减少是否具有改善OA疾病的作用已被确定为该领域最优先的研究议程之一。使用小鼠OA的手术模型，我们已经确定了OA诱导和非诱导滑膜炎之间巨噬细胞和T淋巴细胞数量的显着差异。这一新的数据表明，可能存在独特的细胞靶点和机会窗口，以避免OA的发生并阻止已确立疾病的进展。目前的研究计划将建立在这些发现的基础上，测试消耗特定炎症细胞的治疗效用，并通过转化临床前工作为启动治疗和预防OA的人体临床试验提供平台。

Osteoarthritis (OA) is by far the most prevalent of the joint diseases. There are currently no therapies to halt OA onset or progression. The individual and socioeconomic impact of OA is continuing to grow as the population ages. Finding effective disease-modifying therapies for OA is an international medical research priority. While OA has previously been considered an arthropathy defined by “wear and tear”, there is burgeoning evidence that cellular and molecular pathways are driving disease onset and progression. Inflammation is associated with significantly increased risk of rapid progression of cartilage loss in knees with early OA, and a 3-fold increase in odds of cartilage loss over 30 months follow-up in knees without pre-existing OA. Inflammation is not the byproduct but may actually play a pivotal role in initiating the OA process and its progression. The specific inflammatory events in OA, their change with time and the difference from “non-OA-inducing” inflammation, have yet to be fully elucidated. This proposal aims to establish which components of the OA synovial inflammatory process are critical, thereby identifying new drug targets for treatment of the disease. Determining whether reduction of inflammation has disease-modifying effects in OA has been identified among the highest priority research agendas in the field. Using a surgical model of OA in mice we have identified significant differences in the number of macrophages and T-lymphocytes between OA-inducing and non-inducing synovitis. This novel data suggests there may be unique cellular targets and windows of opportunity to avoid the initiation of OA and to halt the progression of established disease. The current research proposal will build upon these findings, test the therapeutic utility of depleting specific inflammatory cells, and provide the platform for initiating human clinical trials for the treatment and prevention of OA through translating out pre-clinical work.