CCR7 and its ligands in Osteoarthritis

 描述(申请人提供)：骨关节炎(OA)是导致成人残疾的主要原因，其特征是慢性进行性软骨损伤和骨骼重塑。目前的治疗选择有限，不能预防进行性关节损害，与关节功能障碍相关的因素也知之甚少。关节衬里组织(滑膜)的轻度炎症在OA中很常见，并与膝关节功能障碍的严重程度、疼痛和软骨丢失的进展有关。这表明，滑膜炎症可以作为靶点，以减轻OA的症状和进展。我们最近发现趋化因子受体CCR7及其两个配体(CCL19和CCL21)在膝骨性关节炎患者滑膜中的表达，包括早期膝骨性关节炎患者。CCR7参与多种白细胞的招募，提示它可能促进滑膜炎症的发展和持久。在这项提案中，我们将使用公认的内侧半月板失稳(DMM)模型，验证CCR7促进骨关节炎滑膜炎症、软骨损伤和骨重建，并影响骨关节炎相关残疾的发展的假设。在第一个目标中，将监测CCR7表达缺陷(CCR7-/-)小鼠与C57BL/6野生型对照小鼠的OA发展。野生型小鼠也将接受一种融合蛋白的治疗，这种融合蛋白可以中和CCL19的活性。软骨和骨骼的变化将通过组织病理学和微型CT来测量，而滑膜炎症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周进行测量，并与假手术和未手术对照组进行比较。运动和正常活动(攀登、旅行距离、运动速度)将每4周纵向测量一次，直到DMM和假手术后16周，以反映与OA相关的残疾。在第二个目标中，将评估CCR7及其配体在接受DMM或假手术的小鼠关节组织中的表达水平和细胞分布，以及在患有和不患有OA的人类中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CCR7影响骨关节炎的具体机制，并测试药理学的CCR7关节内阻断。

 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.