OA Pathogenesis beyond Cartilage: A preclinical study of the sources of OA pain

软骨以外的 OA 发病机制：OA 疼痛来源的临床前研究

• 批准号: 10401214
• 负责人: Kyle D Allen
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401214
• 关键词: 3-Dimensional; Affect; Animals; Architecture; Arthritis; Awareness; Behavioral Assay; Bone remodeling; CCL2 gene; Cartilage; Cerebrospinal Fluid; Chronic; Classification; Clinical Medicine; Clinical Research; Complex; Confusion; Degenerative polyarthritis; Development; Enzyme-Linked Immunosorbent Assay; Exercise; Exposure to; Fatty acid glycerol esters; Fibrocartilages; Financial compensation; Functional disorder; Gait; Goals; Histological Techniques; Histology; Human; Hypersensitivity skin testing; IL4 gene; IL6 gene; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Interleukin-10; Joint Laxity; Joints; Knee; Knee Osteoarthritis; Lesion; Lighting; Limb structure; Link; Liquid substance; Measures; Mechanics; Medial meniscus structure; Medicine; Methods; Microscopy; Modeling; Moderate Exercise; Motivation; Neurologic; Neuronal Plasticity; Neurons; Optics; Organ; Pain; Pathogenesis; Patients; Pattern; Peripheral Nervous System; Physiological; Physiology; Pre-Clinical Model; Radial; Rattus; Reporting; Research Personnel; Rodent; Rodent Model; Severities; Source; Spinal Ganglia; Structure; Symptoms; Synovial Fluid; Synovial Membrane; Synovitis; arthritic pain; arthropathies; bone; cytokine; disability; fighting; gait examination; improved; innovation; joint inflammation; joint injury; macrophage; meniscal tear; novel; osteoarthritis pain; patch clamp; pre-clinical; preclinical study; subchondral bone; tool; virtual surgery

Project Summary A 2010 public awareness campaign entitled “Fight Arthritis Pain” promoted moving is the best medicine! While clinical studies overwhelmingly confirm exercise is an effective osteoarthritis (OA) treatment, patients often find this advice counterintuitive - “The solution for a painful joint is to use it more?” Part of this confusion is driven by chondrocentric definitions of OA, which imply that more cartilage damage will lead to more pain. However, OA is a `disease of the joint as an organ' with changes occurring throughout the joint. Moreover, factors that affect OA pain and disability occur both within and beyond the articular joint, including changes in joint structure, inflammation, and neuroplasticity. Understanding how these complex factors contribute to the patients' primary concerns - pain and disability - can help identify critical targets for OA therapy. Preclinical OA models should be a powerful tool to help researchers identify physiologic links between OA pathogenesis and symptomology, offering an opportunity to investigate facets of OA that cannot be easily explored in humans. Toward this goal, this proposal will use novel rodent gait analyses and measures of hind limb sensitivity to investigate how changes in joint structure, intra-articular inflammation, and dorsal root ganglia neuroplasticity relate to the development of OA-related pain and disability in rat models of post-traumatic knee OA. First, 3D measures of bony structures will be acquired in our models using a nanoCT, and 3D changes in cartilage and synovium will be assessed using selective plane illumination microscopy (SPIM) on optically- cleared knees (Aim 1). This aim will allow us to investigate relationships between complex 3D joint structures and OA-related pain and disability. Second, the missing link between OA pathogenesis and OA pain is often assumed to be inflammation, which can temporally cycle without major shifts in joint structure. In this proposal, intra-articular inflammation will be directly examined in our models; moreover, the distribution and quantity of macrophages will be examined using SPIM on optically cleared knees (Aim 2). Third, chronic exposure to low grade inflammation can lower the threshold of dorsal root ganglia (DRG) neurons. In this proposal, patch clamp recordings will be used to investigate DRG sensitization subsequent to simulated joint injuries (Aim 3). Additionally, all studies will be collected in the context of OA-related pain and disability, using mechanical hypersensitivity testing and gait analysis to quantify OA-related symptoms in the rat. Finally, a well-established and effective OA therapy - moderate exercise - will be evaluated in each aim to discern how exercise modifies the physiology of the OA-affected knee and leads to improvement in OA-related symptoms. Overall, this approach will use innovative, quantitative methods to simultaneously study joint structure, inflammation, and neuroplasticity in a manner that is not possible in humans, allowing us to assess how these mechanisms contribute to the continuum of OA pain and disability.

项目摘要 2010年的公众意识运动题为“抗击关节炎疼痛”是最好的药物！ 尽管临床研究绝大多数确认运动是一种有效的骨关节炎（OA）治疗，但患者经常 找到此建议违反直觉 - “解决痛苦的关节的解决方案是使用更多？”这种混乱的一部分是驱动的 通过软骨的定义OA，这意味着更多的软骨损害将导致更多的疼痛。然而， OA是一种“关节作为器官”的疾病，整个关节都发生了变化。而且，这是因素 影响OA疼痛和残疾都发生在关节关节内外，包括关节结构的变化， 炎症和神经塑性。了解这些复杂因素如何有助于患者的主要因素 问题 - 疼痛和残疾 - 可以帮助确定OA治疗的关键目标。 临床前OA模型应该是一个强大的工具，可以帮助研究人员确定OA之间的生理联系 发病机理和症状学，提供了调查OA方面的机会 在人类中探索。为了实现这一目标，该提案将使用新颖的啮齿动物分析和后方的措施 肢体敏感性，以研究关节结构，关节内注射和背根神经节的变化如何 在创伤后膝盖大鼠模型中，与OA相关疼痛和残疾的发展有关的神经可塑性 OA。首先，使用纳米CT在我们的模型中获取骨结构的3D测量，3D的变化 将使用选择性平面照明显微镜（SPIM）评估软骨和滑膜 膝盖清除（目标1）。这个目标将使我们能够研究复杂的3D联合结构之间的关系 和与OA相关的疼痛和残疾。其次，OA发病机理与OA疼痛之间的缺失联系通常是 假定为炎症，可以暂时循环，而不会在关节结构上发生重大变化。在此提案中， 关节内炎症将在我们的模型中直接检查；此外，分布和数量 将使用SPIM在光学清除的膝盖上检查巨噬细胞（AIM 2）。第三，长期暴露于低 等级炎症可以降低背根神经（DRG）神经元的阈值。在此提案中，补丁夹 记录将用于研究模拟关节损伤后的DRG敏感性（AIM 3）。 此外，所有研究将在与OA相关的疼痛和残疾的背景下收集 高敏性测试和步态分析，以量化大鼠与OA相关的症状。最后，一个公认的 和有效的OA疗法 - 适度运动 - 将在每个目标中评估如何辨别运动修饰符 OA影响的膝盖的生理学并导致与OA相关的符号的改善。总体而言，这 方法将使用创新的定量方法同时研究联合结构，创新和 神经塑性以人类不可能的方式，使我们能够评估这些机制如何 有助于OA疼痛和残疾的连续性。