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

C-C 趋化因子受体 7 (CCR7) 对滑膜炎和骨关节炎 (OA) 的影响

• 批准号: 9114893
• 负责人: Carla Rose Scanzello
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114893
• 关键词: Address; Adult; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Arthroscopy; Automobile Driving; Award; Bone Spur; Bone remodeling; C57BL/6 Mouse; CC chemokine receptor 7; CCL19 gene; CCL21 gene; Caring; Cartilage; Cells; Centenarian; Chronic; Clinical; Data; Degenerative polyarthritis; Dendritic Cells; Development; Disease; Functional disorder; Future; General Population; Generations; Genetic; Histopathology; Human; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injury; Joints; Knee; Knee Injuries; Knee Osteoarthritis; Knee joint; Knock-out; Lead; Leukocytes; Ligands; Locomotion; Lymphocyte; Measures; Medial meniscus structure; Mediating; Medical; Methods; Modeling; Modification; Motor Activity; Mus; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patients; Population; Reagent; Rehabilitation therapy; Replacement Arthroplasty; Research; Risk; Risk Factors; Role; Services; Severities; Signal Transduction; Source; Speed; Staging; Symptoms; Synovial Cell; Synovial Membrane; Synovitis; Testing; Tissues; Travel; Veterans; Walking; Wild Type Mouse; Work; associated symptom; beta-Chemokines; bone; chemokine receptor; cost; disability; experience; gamma-Chemokines; improved; in vivo; joint destruction; joint function; joint injury; knee pain; member; microCT; monocyte; mouse model; musculoskeletal injury; new therapeutic target; novel; prevent; public health relevance; receptor; reduce symptoms; research study; sham surgery; therapeutic target

 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.

 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，目前的治疗，特别是对于疾病的早期阶段，是有限的，并且不能预防进行性关节损伤。此外，与关节功能障碍相关的因素也很有限。据了解，滑膜的低度炎症在 OA 中很常见，并且与膝关节功能障碍、疼痛和软骨损失的严重程度相关，这表明可以针对滑膜炎症来减轻 OA 的症状和进展。 。我们最近发现趋化因子受体 CCR7 及其两种配体（CCL19 和 CCL21）在膝关节 OA 患者的滑膜中表达，包括因退行性半月板撕裂而接受半月板关节镜检查的早期 OA 患者。多个白细胞群的研究表明它可能促进滑膜炎症的发展和持续。在本提案中，我们将检验 CCR7 的遗传缺失将预防滑膜炎症和滑膜炎症的假设。减少 OA 的软骨损伤以及 OA 相关的关节功能障碍 我们将使用 CCR7 表达缺陷的小鼠 (CCR7 -/-) 与 C57BL/ 进行比较。 6 野生型对照将通过组织病理学和显微 CT 测量软骨和骨骼变化，而滑膜炎将通过对酶促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，并与假手术和年龄匹配的未手术对照进行比较。在第三组实验中，我们将测量运动和正常活动。 DMM 和假手术后每 4 周至 16 周纵向进行一次（攀爬、行进距离、运动速度），比较 CCR7-/- 和 C57BL/6这项研究的结果将支持后续的建议，以了解 CCR7 影响 OA 的具体机制，并测试关节内的药理 CCR7 阻断。