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: 10116963
• 负责人: Kyle D Allen
• 金额: $ 35.1万
• 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/10116963
• 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.

项目概要 2010 年一项题为“对抗关节炎疼痛”的公众意识活动提倡运动是最好的良药！ 虽然临床研究绝大多数证实运动是一种有效的骨关节炎 (OA) 治疗方法，但患者经常 觉得这个建议违反直觉——“解决关节疼痛的办法就是更多地使用它？” 根据 OA 的软骨中心定义，这意味着更多的软骨损伤将导致更多的疼痛。 OA 是一种“关节作为器官的疾病”，其变化发生在整个关节中。 影响 OA 疼痛和残疾发生在关节内外，包括关节结构的变化， 了解这些复杂因素如何影响患者的原发性。 关注点——疼痛和残疾——可以帮助确定骨关节炎治疗的关键目标。 临床前 OA 模型应该是帮助研究人员识别 OA 之间的生理联系的强大工具 发病机制和症状学，为研究 OA 的各个方面提供了机会，而这些方面不容易 为了实现这一目标，该提案将使用新颖的啮齿动物步态分析和后肢测量。 肢体敏感性，以研究关节结构、关节内炎症和背根神经节的变化 神经可塑性与创伤后膝关节大鼠模型中 OA 相关疼痛和残疾的发展有关 首先，将使用 nanoCT 在我们的模型中获取骨结构的 3D 测量，并进行 3D 变化。 将使用选择性平面照明显微镜（SPIM）在光学上评估软骨和滑膜 清理膝盖（目标 1）。这个目标将使我们能够研究复杂的 3D 关节结构之间的关系。 其次，OA 发病机制和 OA 疼痛之间往往缺乏联系。 假设是炎症，它可以暂时循环，而关节结构不会发生重大变化。 此外，我们的模型将直接检查关节内炎症的分布和数量； 将使用 SPIM 在光学透明的膝盖上检查巨噬细胞（目标 2）。 等级炎症可以降低背根神经节（DRG）神经元的阈值。在这个提议中，膜片钳。 记录将用于研究模拟关节损伤后 DRG 的敏感性（目标 3）。 此外，所有研究都将在 OA 相关疼痛和残疾的背景下收集，使用机械方法 最后，通过超敏反应测试和步态分析来量化大鼠的 OA 相关症状。 有效的 OA 治疗（适度运动）将在每个目标中进行评估，以了解运动如何改变 总体而言，这可以改善受 OA 影响的膝盖的生理机能，并改善 OA 相关症状。 该方法将使用创新的定量方法来同时研究关节结构、炎症和 神经可塑性以人类不可能的方式进行，使我们能够评估这些机制如何 导致 OA 疼痛和残疾的连续性。