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（由申请人提供）：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伤和骨重塑。目前的治疗选择是有限的，不能防止进行性关节损伤，关节功能障碍的相关因素知之甚少。关节衬里组织（滑膜）的低度炎症在OA中很常见，并且与膝关节功能障碍、疼痛和软骨损失进展的严重程度相关。这表明，滑膜炎症可能是有针对性的，以减少症状和OA的进展。我们最近发现趋化因子受体CCR 7及其两种配体（CCL 19和CCL 21）在膝关节OA患者（包括早期OA膝关节OA患者）的滑膜中表达。CCR 7参与多个白细胞群体的募集，这表明它可能促进滑膜炎症的发展和持续。在本提案中，我们将使用完善的内侧半月板（DMM）小鼠不稳定模型来检验CCR 7促进OA中的滑膜炎症、软骨损伤和骨重建，并影响OA相关残疾的发展的假设。在第一个目标中，与C57 BL/6野生型对照相比，将在CCR 7表达缺陷的小鼠（CCR 7-/-）中监测OA发展。野生型小鼠也将用抵消CCL 19活性的融合蛋白处理。软骨和骨变化将通过组织病理学和显微CT测量，而滑膜炎症将通过基因表达和流式细胞术测量。将在DMM手术后2、4、8和16周测量这些结局，并与假手术和未手术对照组进行比较。将每4周一次纵向测量运动和正常活动（攀爬、行进距离、运动速度），直至DMM和假手术后16周，以反映OA相关残疾。在第二个目标中，将在来自经受DMM或假手术的小鼠的关节组织中以及在患有和不患有OA的人中评估CCR 7及其配体的表达水平和细胞分布。这项研究的结果将支持后续的建议，以了解CCR 7影响OA的具体机制，并测试关节内CCR 7阻断的药理学作用。