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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

基本信息

批准号：
10399328
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
项目类别：
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/10399328
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

项目摘要

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.

项目总结