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，导致功能受损和生活质量损失，也是美国老年人口流动性受损的主要原因之一。我们缺乏总体上慢性疼痛的机制，尤其是与OA相关的慢性疼痛，这是当前可用治疗方案的总体无效性。缓解严重的OA疼痛仍然是未满足的医疗需求，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有重大影响，但我们对人OA疼痛机制的理解仍然很差。该提案的长期目标是定义OA疼痛的起源和机制，从而可以鉴定新靶标，并开发新的疗法和生物标志物来实现OA疼痛。引人入胜的激励数据以及新颖的转基因小鼠为即时研究和在这个高度研究的领域的快速发展创造了独特的机会。这些研究的目的是三个方面：1）使用经过验证的鼠OA模型，内侧半月板（DMM）的稳定，以定量测量疼痛并确定关节组织中的同时细胞和结构改变及其感觉神经支配（外围成分和背根神经节）。目的是使用评估机械异常性异常，自发疼痛行为和步态的技术对疾病的疼痛进行定性和定量评估。疼痛措施的详细关联将与所有关节组织（软骨，骨骼，滑膜和半月板）的病理变化以及与关节和背根神经节中传入神经突的数量和位置发生变化相关的病理变化; 2）确定抑制ADAMTS-5对DMM模型中结构关节和神经元变化的疼痛的影响。通过使用ADAMTS5 NULL小鼠和b）使用有效和选择性抑制剂对ADAMTS-5进行药理学抑制，将在体内实现抑制作用a）。没有活性ADAMTS-5可预防DMM模型中的OA进展。 ADAMTS-5抑制剂正在作为改良疾病的OA药物开发，而没有明确了解其影响疼痛的潜力。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，以及疾病发作后多长时间与OA结构变化相关的疼痛是可逆的，或者在疼痛的哪个阶段变得不可逆转。预计这里的发现对人OA的疼痛管理具有重要意义。 3）通过时间分析伤害感受途径，神经胶质激活和透明质片段的分子标记，参与DMM模型中OA相关疼痛发作和慢性的分子途径。具体而言，将探索NGF介导的和MCP-1介导的伤害感受器途径的时间作用。与这些动物研究有关的基因将为大型人类OA队列中具有已知疼痛和残疾度量（例如WOMAC评分）的遗传连锁分析提供基础。 公共卫生相关性：骨关节炎伴随的疼痛代表了主要的未满足医疗需求。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。