CCR7 and its ligands in Osteoarthritis

CCR7 及其配体在骨关节炎中的作用

• 批准号: 9022408
• 负责人: Carla Rose Scanzello
• 金额: $ 17.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022408
• 关键词: Address; Adult; Animal Model; Anti-Inflammatory Agents; Arthralgia; Arthritis; Automobile Driving; Bone remodeling; CCL19 gene; CCL21 gene; Cartilage; Chimeric Proteins; Chronic; Clinical; Confocal Microscopy; Data; Degenerative polyarthritis; Dendritic Cells; Development; Disease; Flow Cytometry; Functional disorder; Gene Expression; Generations; Health; Histopathology; Human; Immunoglobulin G; Incidence; Inflammation; Inflammatory; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knee joint; Knock-out; Lead; Leukocytes; Ligands; Locomotion; Lymphocyte; Measures; Medial meniscus structure; Medical; Meniscus structure of joint; Messenger RNA; Methods; Modeling; Monitor; Mus; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patients; Pattern; Population; Proteins; Rehabilitation therapy; Replacement Arthroplasty; Research; Risk; Role; Severities; Speed; Staging; Symptoms; Synovial Cell; Synovial Membrane; Synovitis; Testing; Time; Tissues; Transcript; Travel; Wild Type Mouse; advanced disease; bone; cartilage degradation; chemokine; chemokine receptor; disability; effective therapy; experience; improved; joint destruction; joint injury; light microscopy; microCT; monocyte; mouse model; new therapeutic target; novel; prevent; receptor; reduce symptoms; sham surgery; therapeutic target; treatment strategy; vibration

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a leading cause of disability in adults, and is characterized by chronic progressive cartilage damage and bony remodeling. Current treatment options are limited, do not prevent progressive joint damage, and factors related to joint dysfunction are poorly understood. Low-grade inflammation of the joint lining tissue (synovial membrane) is common in OA, and has been associated with severity of knee joint dysfunction, pain, and progression of cartilage loss. This suggests that synovial inflammation could be targeted to reduce both symptoms and progression of OA. We have recently identified expression of the chemokine receptor CCR7 and its two ligands (CCL19 and CCL21) in the synovial membrane of knee OA patients, including patients with early-stage OA knee OA. CCR7 is involved in the recruitment of multiple leukocyte populations suggesting it may promote development and perpetuation of synovial inflammation. In this proposal, we will test the hypothesis that CCR7 promotes synovial inflammation, cartilage damage and bone remodeling in OA, and impacts development of OA related disability, using the well-established murine destabilization of the medial meniscus (DMM) model. In the first aim, OA development will be monitored in mice deficient in CCR7 expression (CCR7 -/-) compared to C57BL/6 wild-type controls. Wild-type mice will also be treated with a fusion protein which counteracts the activity of CCL19. Cartilage and bone changes will be measured by histopathology and micro-CT, while synovial inflammation will be measured by gene expression and flow cytometry. These outcomes will be measured at 2, 4, 8, and 16 weeks post-DMM surgery, and compared to sham-operated and unoperated controls. Locomotion and normal activity (climbing, distance traveled, speed of locomotion) will be measured longitudinally every 4 weeks up to 16 weeks post- DMM and sham surgery, as a reflection of OA-related disability. In the second aim, expression levels and cellular distribution of CCR7 and its ligands will be evaluated in joint tissues from mice subjected to DMM or sham surgery, and in humans with and without OA. Results of this study will support subsequent proposals to understand specific mechanisms by which CCR7 impacts OA, and test pharmacologic CCR7 blockade intra-articularly.

 描述（由适用提供）：骨关节炎（OA）是成人残疾的主要原因，其特征是慢性进行性软骨损害和奖励重塑。当前的治疗方案是有限的，不能防止进行性关节损害，并且与关节功能障碍有关的因素也很少理解。关节内膜组织（滑膜）的低度炎症在OA中很常见，并且与膝关节功能障碍，疼痛和软骨损失的进展有关。这表明可以针对滑膜注射以减少OA的症状和进展。我们最近确定了趋化因子受体CCR7及其两种配体（CCL19和CCL21）在膝关节OA患者的滑膜中的表达，包括早期OA膝关节OA的患者。 CCR7参与了多个白细胞种群的募集，这表明它可能促进滑膜感染的发育和延续。在此提案中，我们将使用媒介拟扫（DMM）模型的鼠类破坏稳定的模型，检验了CCR7促进OA中促进滑膜感染，软骨损伤和骨骼重塑的假设。在第一个目标中，与C57BL/6野生型对照相比，将在缺乏CCR7表达（CCR7 - / - ）的小鼠中监测OA发育。野生型小鼠还将用融合蛋白来处理，该融合蛋白应对CCL19的活性。软骨和骨骼变化将通过组织病理学和微CT来衡量，而滑膜注射将通过基因表达和流式细胞术来测量。这些结果将在DMM手术后2、4、8和16周测量，并与假手术和非手术对照进行比较。运动和正常活动（攀爬，距离旅行，运动速度）将在DMM和假手术后每4周纵向测量，以反映与OA相关的残疾。在第二个目的中，将在接受DMM或假手术的小鼠以及有和没有OA的人类的关节时机中评估CCR7及其配体的表达水平和细胞分布。这项研究的结果将支持随后的建议，以了解CCR7影响OA的特定机制，并在关节内测试药物CCR7阻断。