The Impact of C-C Chemokine Receptor 7 (CCR7) on Synovitis and Osteoarthritis (OA)

 描述(由申请人提供)： 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。目前的治疗方法，特别是对疾病的早期阶段，是有限的，并不能防止进行性关节损害。此外，与关节功能障碍相关的因素也知之甚少。滑膜的低度炎症在骨性关节炎中很常见，并与严重的膝关节功能障碍、疼痛和软骨丧失的进展有关。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)在膝关节骨性关节炎患者滑膜中的表达，包括因退行性半月板撕裂而行半月板关节镜检查的早期骨性关节炎患者。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，我们将检验CCR7基因缺失将预防滑膜炎症和减少OA的软骨损伤以及OA相关的关节功能障碍的假说。我们将使用典型的小鼠内侧半月板失稳(DMM)模型。CCR7表达缺陷的小鼠(CCR7-/-)将与C57BL/6野生型对照进行比较。软骨和骨骼的变化将通过组织病理学和微型CT来测量，而滑膜炎将通过对显微解剖组织中酶释放的细胞进行流式细胞术分析来测量。这些结果将在DMM手术后2、4、8和16周进行测量，并与假手术组和年龄匹配的未手术对照组进行比较。在第三组实验中，我们将每4周纵向测量一次运动和正常活动(攀登、旅行距离、运动速度)，直到DMM和Sham手术后16周，比较CCR7-/-和C57BL/6年龄匹配的小鼠。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, is characterized by chronic progressive cartilage damage. Current treatment, particularly for early stages of disease, is limited and does not prevent progressive joint damage. Furthermore, factors related to joint dysfunction are poorly understood. Low-grade inflammation of the 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 presenting for meniscal arthroscopy due to degenerative meniscal tears. 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 genetic loss of CCR7 will prevent synovial inflammation and diminish cartilage damage in OA, as well as OA-related joint dysfunction. We will use the well-characterized murine destabilization of the medial meniscus (DMM) model. Mice deficient in CCR7 expression (CCR7 -/-) will be compared to C57BL/6 wild-type controls. Cartilage and bone changes will be measured by histopathology and micro-CT while synovitis will be measured by flow cytometric analysis of enzymatically released cells from microdissected tissues. These outcomes will be measured at 2, 4, 8, and 16 weeks post-DMM surgery, and compared to sham-operated and age-matched unoperated controls. In a third set of experiments, we will measure locomotion and normal activity (climbing, distance traveled, speed of locomotion) longitudinally every 4 weeks up to 16 weeks post- DMM and sham surgery, comparing CCR7-/- and C57BL/6 age-matched mice. Results of this study will support subsequent proposals to understand specific mechanisms by which CCR7 impacts OA, and test pharmacologic CCR7 blockade intra-articularly.