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。目前还没有阻止骨性关节炎发病或进展的疗法。随着人口老龄化，开放式学习对个人和社会经济的影响持续增长。为骨性关节炎寻找有效的疾病修正疗法是国际医学研究的重点。尽管骨关节炎以前被认为是一种由“磨损”定义的关节病，但越来越多的证据表明，细胞和分子途径正在推动疾病的发生和发展。炎症与早期有骨性关节炎的膝关节软骨丢失的快速进展的风险显著增加有关，而在没有预先存在的骨性关节炎的膝关节在30个月的随访期内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。骨性关节炎中的具体炎症事件、其随时间的变化以及与“非骨性骨性关节炎”炎症的区别尚不完全清楚。这项建议旨在确定骨性关节炎滑膜炎症过程中的哪些成分是关键的，从而确定治疗该病的新的药物靶点。确定减少炎症是否对骨关节炎具有疾病改善作用已被确定为该领域最优先的研究议程之一。利用小鼠骨性关节炎的外科模型，我们发现骨性关节炎诱导性滑膜炎和非诱发性滑膜炎在巨噬细胞和T淋巴细胞的数量上有显着差异。这一新颖的数据表明，可能存在独特的细胞靶点和机会之窗，以避免OA的启动并阻止既定疾病的进展。目前的研究计划将以这些发现为基础，测试清除特定炎症细胞的治疗效用，并通过转化临床前工作，为启动治疗和预防骨性关节炎的人类临床试验提供平台。

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.