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: 10564335
• 负责人: Kyle D Allen
• 金额: $ 7.67万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10564335
• 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年一项名为“抗击关节炎疼痛”的宣传活动宣传感动是最好的良药！ 虽然临床研究压倒性地证实运动是一种有效的骨关节炎(OA)治疗方法，但患者往往 我觉得这个建议有违常理--“关节痛的解决办法就是多用它？”造成这种混乱的部分原因是 通过以软骨为中心的定义，这意味着更多的软骨损伤将导致更多的疼痛。然而， 骨性关节炎是一种“关节作为器官的疾病”，其变化发生在整个关节。此外，这些因素 影响骨性关节炎疼痛和残疾发生在关节内外，包括关节结构的改变， 炎症和神经可塑性。了解这些复杂因素是如何影响患者的原发病的 担忧--疼痛和残疾--有助于确定OA治疗的关键目标。 临床前骨性关节炎模型应该是帮助研究人员确定骨性关节炎之间生理联系的有力工具 发病机制和症状学，提供了一个机会来研究OA的一些不容易的方面 在人类身上进行了探索。为此，本建议将采用新颖的啮齿动物步态分析和后处理措施 肢体敏感性研究关节结构、关节内炎症和背根神经节的变化 神经可塑性与膝关节创伤后骨性关节炎相关疼痛和残疾的发展 骨关节炎。首先，我们将使用纳米CT在我们的模型中获取骨骼结构的3D测量，并在 软骨和滑膜将使用选择性平面照明显微镜(SPIM)在光学上进行评估- 清理膝盖(目标1)。这一目标将使我们能够研究复杂的3D关节结构之间的关系 以及与骨关节炎相关的疼痛和残疾。其次，骨性关节炎发病机制和骨性关节炎疼痛之间缺失的环节通常是 假定为炎症，可以暂时循环，关节结构不会发生重大变化。在这份提案中， 在我们的模型中将直接检查关节内的炎症；此外， 巨噬细胞将在光学透明的膝盖上使用SPIM进行检查(目标2)。第三，长期暴露在低水平 分级炎症可降低背根神经节(DRG)神经元阈值。在本方案中，膜片钳 录音将用于研究模拟关节损伤后DRG的敏感化(目标3)。 此外，所有研究将收集与骨性关节炎相关的疼痛和残疾，使用机械 超敏反应测试和步态分析以量化大鼠的骨性关节炎相关症状。最后，一个久负盛名的 有效的骨性关节炎疗法--适度运动--将在每个目标上进行评估，以弄清运动如何改变 改善膝关节的生理功能，改善膝关节的相关症状。总体而言，这 方法将使用创新的定量方法来同时研究关节结构、炎症和 神经可塑性在人类中是不可能的，这使我们能够评估这些机制是如何 对骨性关节炎疼痛和残疾的连续体做出贡献。

项目成果

African Spiny Mice (Acomys) Exhibit Mild Osteoarthritis Following Meniscal Injury.

• DOI: 10.1177/19476035221149146
• 发表时间: 2023-03
• 期刊: CARTILAGE
• 影响因子: 2.8
• 作者: Chan, Kiara M.;Thurlow, Nat A.;Maden, Malcolm;Allen, Kyle D.
• 通讯作者: Allen, Kyle D.

High frequency alternating current neurostimulation decreases nocifensive behavior in a disc herniation model of lumbar radiculopathy.

高频交替的电流神经刺激会降低腰椎椎间盘突出模型中的单化行为。

• DOI: 10.1186/s42234-023-00119-0
• 发表时间: 2023-07-12
• 期刊: Bioelectronic medicine
• 作者: Dewberry, Lauren Savannah;Porche, Ken;Koenig, Travis;Allen, Kyle D;Otto, Kevin J
• 通讯作者: Otto, Kevin J

Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase.

• DOI: 10.1038/s41551-023-01025-1
• 发表时间: 2023-09
• 期刊: Nature biomedical engineering
• 影响因子: 28.1

The clearance and biodistribution of magnetic composite nanoparticles in healthy and osteoarthritic rat knees.

• DOI: 10.1016/j.jconrel.2020.01.052
• 发表时间: 2020-05-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Partain BD;Unni M;Rinaldi C;Allen KD
• 通讯作者: Allen KD

Factors affecting the reliability of behavioral assessments for rodent osteoarthritis models.

• DOI: 10.1177/0023677219867715
• 发表时间: 2020-08
• 期刊: Laboratory animals
• 影响因子: 2.4
• 作者: Jacobs BY;Allen KD
• 通讯作者: Allen KD