MCP-1/CCR2 Signaling in the Maintenance of OA Pathology and Associated Pain

MCP-1/CCR2 信号转导在维持 OA 病理学和相关疼痛中的作用

• 批准号: 8455056
• 负责人: Rachel Elizabeth Miller
• 金额: $ 5.67万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455056
• 关键词: Acute; Affinity; Analgesics; Arthralgia; Behavior; C57BL/6 Mouse; Cellular Infiltration; Chemotactic Factors; Chronic; Chronic Phase; Data; Degenerative polyarthritis; Disease; Esthesia; Goals; Grant; Histopathology; In Situ Hybridization; Intervention; Joints; Knee joint; Knockout Mice; Lead; Locomotion; Maintenance; Manuscripts; Measures; Mechanics; Medial meniscus structure; Medical; Mentors; Modeling; Molecular; Molecular Analysis; Monocyte Chemoattractant Protein-1; Mouse Strains; Mus; Musculoskeletal Pain; Musculoskeletal System; Nervous system structure; Neuraxis; Neuroglia; Neurons; Operative Surgical Procedures; Pain; Pathology; Pathway interactions; Pattern; Peripheral; Persistent pain; Pharmaceutical Preparations; Preparation; Purinoceptor; Reporter; Research; Research Personnel; Signal Transduction; Spinal Ganglia; Staging; Testing; Therapeutic Effect; Time; Training; Travel; Wild Type Mouse; Writing; base; chronic pain; cytokine; in vivo Model; insight; joint destruction; joint injury; macrophage; mechanical allodynia; monocyte chemoattractant protein 1 receptor; mouse model; pain behavior; public health relevance; response; skills; small molecule; transmission process

DESCRIPTION (provided by applicant): Pain in osteoarthritis (OA) represents a major unmet medical need. Our understanding of the pathways that generate and maintain pain in OA remains poor. Cumulative data suggest that OA pain is generated through local mechanisms in the joint, while sensitization of the peripheral and central nervous system amplifies the pain and contributes to its chronicity. Destabilization of the medial meniscus (DMM) in wild-type C57BL/6 mice provides an in vivo model where joint pathology progresses slowly over 16 weeks, thus enabling the study of temporal changes in pain sensation in association with progressive joint pathology. We have generated compelling data that DMM-associated pain behavior presents in two stages: mechanical allodynia begins early, progresses up to 4 weeks, and is maintained for 16 weeks after surgery; stage two begins at week 8, with changes indicative of persistent pain, including decreased locomotion (distance traveled, climbing). Analysis of molecular changes in the innervating dorsal root ganglia (DRG) shows that monocyte chemoattractant protein 1 (MCP-1) and its high affinity receptor, CCR2, are highly upregulated in the DRG 8 weeks post DMM. Ccr2 null mice initially develop mechanical allodynia, but it begins to resolve 8 weeks post DMM. Pain behaviors indicative of persistent pain (decreased locomotion) do not occur in these mice, and they are partially protected from joint destruction by 16 weeks post DMM. Therefore, the goal of this proposal is to test the Central Hypothesis: MCP-1/CCR2 activity is a key driver for the maintenance of pain and structural damage in the DMM model. Aim 1 seeks to determine the function of MCP-1/CCR2 in establishing chronic OA pain and joint pathology post DMM. Aim 1a will identify expression of MCP-1 and CCR2 by neurons, glia, and macrophages in the DRG and will examine downstream functional effects. Aim 1b will compare the progression of pathology, cellular infiltration, and cytokine expression in the knee joint of WT and Ccr2 null mice after DMM. Aim 2 seeks to test the hypothesis that CCR2 blockade reduces pain behavior following DMM surgery. This aim will test the ability of a CCR2 receptor antagonist to 1) Have an immediate analgesic effect on mechanical allodynia, and 2) Have disease-modifying effects on persistent OA pain behaviors and joint pathology by long-term intervention beginning at early or late stages of OA. Effects on pain behavior will be quantified on a bi-weekly basis by the following established measures (mechanical allodynia and locomotion); Effects on joint damage will be analyzed by histopathology.

描述（由申请人提供）：骨关节炎 (OA) 疼痛是一项未满足的主要医疗需求。我们对骨关节炎疼痛产生和维持的途径的了解仍然很少。累积数据表明，骨关节炎疼痛是通过关节的局部机制产生的，而周围和中枢神经系统的敏化会放大疼痛并导致其慢性化。野生型 C57BL/6 小鼠内侧半月板 (DMM) 的不稳定提供了一个体内模型，其中关节病理在 16 周内缓慢进展，从而能够研究与进展性关节病理相关的疼痛感觉的时间变化。我们已经生成了令人信服的数据，表明 DMM 相关的疼痛行为呈现两个阶段：机械性异常性疼痛早期开始，进展长达 4 周，并在术后维持 16 周；第二阶段从第 8 周开始，出现持续疼痛的变化，包括运动能力下降（行走距离、攀爬）。对支配背根神经节 (DRG) 的分子变化的分析表明，DMM 后 8 周，单核细胞趋化蛋白 1 (MCP-1) 及其高亲和力受体 CCR2 在 DRG 中高度上调。 Ccr2缺失小鼠最初出现机械异常性疼痛，但在DMM后8周开始缓解。这些小鼠没有出现表明持续疼痛（运动减少）的疼痛行为，并且在 DMM 后 16 周时，它们得到部分保护，免受关节破坏。因此，该提案的目标是检验中心假设：MCP-1/CCR2 活性是 DMM 模型中维持疼痛和结构损伤的关键驱动因素。目标 1 旨在确定 MCP-1/CCR2 在建立 DMM 后慢性 OA 疼痛和关节病理学方面的功能。目标 1a 将鉴定 DRG 中神经元、神经胶质细胞和巨噬细胞的 MCP-1 和 CCR2 表达，并检查下游功能影响。目标 1b 将比较 DMM 后 WT 和 Ccr2 null 小鼠膝关节的病理进展、细胞浸润和细胞因子表达。目标 2 旨在检验 CCR2 阻断可减少 DMM 手术后疼痛行为的假设。该目标将测试 CCR2 受体拮抗剂的能力：1) 对机械异常性疼痛具有立即镇痛作用，2) 通过从早期或晚期开始的长期干预，对持续性 OA 疼痛行为和关节病理具有缓解疾病的作用OA。将通过以下既定措施（机械异常性疼痛和运动）每两周对疼痛行为的影响进行量化；将通过组织病理学分析对关节损伤的影响。