Molecular Pathways of Pain Generation in Osteoarthritis

骨关节炎疼痛产生的分子途径

• 批准号: 8214516
• 负责人: Anne-Marie Malfait
• 金额: $ 33.75万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214516
• 关键词: ADAMTS; Accounting; Affect; Animals; Area; Biological Markers; C57BL/6 Mouse; CCL2 gene; CSPG3 gene; Cartilage; Cells; Chronic; Collaborations; Core Facility; Data; Degenerative polyarthritis; Development; Disease; Elderly; Event; Gait; Generations; Genes; Goals; Health; Healthcare; Human; Joints; Knockout Mice; Lead; Location; London; Measurement; Measures; Medial meniscus structure; Mediating; Mediator of activation protein; Medical; Meniscus structure of joint; Messenger RNA; Modeling; Molecular; Mus; Musculoskeletal Pain; Neurites; Neurons; Nociception; Nociceptors; Onset of illness; Ontario; Operative Surgical Procedures; Pain; Pain Measurement; Pain management; Pathway interactions; Peripheral; Pharmaceutical Preparations; Population; Process; Proteins; Proteolysis; Quality of life; Relative (related person); Reporter; Research Personnel; Rheumatology; Role; Sensory; Spinal Ganglia; Staging; Symptoms; Synovial Membrane; Techniques; Testing; Tissues; Universities; aggrecan; base; bone; brevican; chronic pain; cohort; college; disability; extracellular; genetic linkage analysis; in vivo; inhibitor/antagonist; loss of function; mechanical allodynia; medical schools; molecular marker; nerve supply; novel; pain behavior; public health relevance; response; spatial relationship; spontaneous pain; versican

DESCRIPTION (provided by applicant): Pain is the major symptom in osteoarthritis (OA), contributing to impaired function and loss of quality of life, and one of the leading causes of impaired mobility in the elderly population in the US. Our lack of understanding the mechanisms underlying chronic pain in general, and chronic pain associated with OA in particular, accounts for the general ineffectiveness of currently available treatment options. Relief from severe OA pain remains an unmet medical need and a major reason for seeking surgical intervention. In spite of its major impact on quality of life and health care management, our understanding of the mechanisms of pain in human OA remains very poor. The long-term goal of this proposal is to define origins and mechanisms of pain in OA, thus enabling identification of new targets, and development of new therapies and biomarkers for OA pain. Compelling motivating data, along with novel genetically modified mice, have created a unique opportunity for immediate studies and rapid advances in this highly understudied area. The goal of these studies is three-fold: 1) Use a validated murine OA model, destabilization of the medial meniscus (DMM), to quantitatively measure pain and determine concurrent cellular and structural alterations in joint tissues and their sensory innervation (peripheral component and dorsal root ganglia). The goal is to make a qualitative and quantitative assessment of pain in the 16-week course of the disease using techniques that evaluate mechanical allodynia, spontaneous pain behavior and gait. A detailed correlation of pain measures will be made with pathological changes in all joint tissues (cartilage, bone, synovium, and meniscus) and with concomitant changes in the number and location of afferent neurites in the joint and dorsal root ganglia; 2) Determine the effect of inhibiting ADAMTS-5 on pain detected in association with structural joint and neuronal changes in the DMM model. Inhibition will be achieved in vivo a) by using Adamts5 null mice and b) by pharmacological inhibition of ADAMTS-5 with potent and selective inhibitors. The absence of active ADAMTS-5 protects against OA progression in the DMM model. ADAMTS-5 inhibitors are being developed as disease-modifying OA drugs, without clear understanding of their potential to affect pain. These studies should allow us to determine whether these inhibitors will also affect pain, and how long after onset of disease the pain associated with OA structural changes is reversible or at what stage the pain has become irreversible. Findings here are expected to have important implications for pain management in human OA; 3) Dissect molecular pathways participating in onset and chronicity of OA-related pain in the DMM model, through temporal analysis of molecular markers of nociceptive pathways, glial activation, and hyalectan fragments. Specifically, the temporal role of the NGF-mediated and the MCP-1-mediated nociceptor pathway will be explored. Genes implicated in these animal studies will provide the basis for genetic linkage analysis in large human OA cohorts with known pain and disability measures such as the WOMAC score. PUBLIC HEALTH RELEVANCE: The pain that accompanies osteoarthritis represents a major unmet medical need. Understanding the cellular and molecular mechanisms that lead to chronic pain in osteoarthritis will have a major impact on treatments for pain relief, with potential applications to other musculoskeletal pain.

描述（由申请人提供）：疼痛是骨关节炎 (OA) 的主要症状，会导致功能受损和生活质量下降，也是美国老年人活动能力受损的主要原因之一。我们对一般慢性疼痛，特别是与骨关节炎相关的慢性疼痛的机制缺乏了解，导致目前可用的治疗方案普遍无效。缓解严重的骨关​​节炎疼痛仍然是一个未满足的医疗需求，也是寻求手术干预的主要原因。尽管它对生活质量和医疗保健管理产生重大影响，但我们对人类骨关节炎疼痛机制的了解仍然非常少。该提案的长期目标是确定 OA 疼痛的起源和机制，从而能够识别新靶标，开发 OA 疼痛的新疗法和生物标志物。令人信服的激励数据，以及新型转基因小鼠，为这一高度研究不足的领域的立即研究和快速进展创造了独特的机会。这些研究的目标有三个：1) 使用经过验证的小鼠 OA 模型（内侧半月板 (DMM) 不稳定）来定量测量疼痛并确定关节组织及其感觉神经支配（外周成分和感觉神经支配）中并发的细胞和结构变化。背根神经节）。目标是使用评估机械性异常性疼痛、自发性疼痛行为和步态的技术，对 16 周病程中的疼痛进行定性和定量评估。疼痛测量的详细关联将与所有关节组织（软骨、骨、滑膜和半月板）的病理变化以及关节和背根神经节中传入神经突的数量和位置的伴随变化进行相关； 2) 确定抑制 ADAMTS-5 对 DMM 模型中检测到的与结构关节和神经元变化相关的疼痛的影响。 a) 通过使用 Adamts5 null 小鼠和 b) 通过使用有效和选择性抑制剂对 ADAMTS-5 进行药理学抑制，可在体内实现抑制。缺乏活性 ADAMTS-5 可防止 DMM 模型中的 OA 进展。 ADAMTS-5 抑制剂正在被开发为改善 OA 疾病的药物，但对其影响疼痛的潜力尚不清楚。这些研究应该使我们能够确定这些抑制剂是否也会影响疼痛，以及在疾病发作后多长时间与骨关节炎结构变化相关的疼痛是可逆的，或者在什么阶段疼痛变得不可逆。这里的研究结果预计将对人类 OA 的疼痛管理产生重要影响； 3) 通过对伤害感受途径、神经胶质活化和透明质酸片段的分子标记物的时间分析，剖析参与 DMM 模型中 OA 相关疼痛的发作和慢性化的分子途径。具体来说，将探讨 NGF 介导的和 MCP-1 介导的伤害感受器通路的时间作用。这些动物研究中涉及的基因将为大型人类 OA 队列中已知的疼痛和残疾指标（例如 WOMAC 评分）的遗传连锁分析提供基础。 公共卫生相关性：骨关节炎带来的疼痛是一项未得到满足的重大医疗需求。了解导致骨关节炎慢性疼痛的细胞和分子机制将对缓解疼痛的治疗产生重大影响，并可能应用于其他肌肉骨骼疼痛。