Tang Shirley N, Walter Benjamin A, Heimann Mary K, Gantt Connor C, Khan Safdar N, Kokiko-Cochran Olga N, Askwith Candice C, Purmessur Devina
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States.
Department of Orthopaedics, Wexner Medical Center, The Ohio State University, Columbus, OH, United States.
Front Pain Res (Lausanne). 2022 Jun 22;3:894651. doi: 10.3389/fpain.2022.894651. eCollection 2022.
Low back pain is a leading cause of disability worldwide and studies have demonstrated intervertebral disc (IVD) degeneration as a major risk factor. While many models have been developed and used to study IVD pathophysiology and therapeutic strategies, the etiology of IVD degeneration is a complex multifactorial process involving crosstalk of nearby tissues and systemic effects. Thus, the use of appropriate models is necessary to fully understand the associated molecular, structural, and functional changes and how they relate to pain. Mouse models have been widely adopted due to accessibility and ease of genetic manipulation compared to other animal models. Despite their small size, mice lumbar discs demonstrate significant similarities to the human IVD in terms of geometry, structure, and mechanical properties. While several different mouse models of IVD degeneration exist, greater standardization of the methods for inducing degeneration and the development of a consistent set of output measurements could allow mouse models to become a stronger tool for clinical translation. This article reviews current mouse models of IVD degeneration in the context of clinical translation and highlights a critical set of output measurements for studying disease pathology or screening regenerative therapies with an emphasis on pain phenotyping. First, we summarized and categorized these models into genetic, age-related, and mechanically induced. Then, the outcome parameters assessed in these models are compared including, molecular, cellular, functional/structural, and pain assessments for both evoked and spontaneous pain. These comparisons highlight a set of potential key parameters that can be used to validate the model and inform its utility to screen potential therapies for IVD degeneration and their translation to the human condition. As treatment of symptomatic pain is important, this review provides an emphasis on critical pain-like behavior assessments in mice and explores current behavioral assessments relevant to discogenic back pain. Overall, the specific research question was determined to be essential to identify the relevant model with histological staining, imaging, extracellular matrix composition, mechanics, and pain as critical parameters for assessing degeneration and regenerative strategies.
腰痛是全球致残的主要原因，研究表明椎间盘（IVD）退变是一个主要风险因素。虽然已经开发并使用了许多模型来研究IVD病理生理学和治疗策略，但IVD退变的病因是一个复杂的多因素过程，涉及附近组织的相互作用和全身影响。因此，使用合适的模型对于全面了解相关的分子、结构和功能变化以及它们与疼痛的关系是必要的。与其他动物模型相比，小鼠模型由于易于获取和基因操作而被广泛采用。尽管小鼠体型小，但小鼠腰椎间盘在几何形状、结构和力学性能方面与人类IVD有显著相似之处。虽然存在几种不同的IVD退变小鼠模型，但诱导退变方法的更大标准化以及一套一致的输出测量方法的开发可以使小鼠模型成为临床转化的更强大工具。本文在临床转化的背景下综述了当前的IVD退变小鼠模型，并强调了一组关键的输出测量方法，用于研究疾病病理学或筛选再生疗法，重点是疼痛表型分析。首先，我们将这些模型总结并分类为基因性、年龄相关性和机械诱导性。然后，比较这些模型中评估的结果参数，包括分子、细胞、功能/结构以及对诱发痛和自发痛的疼痛评估。这些比较突出了一组潜在的关键参数，可用于验证模型并告知其在筛选IVD退变潜在疗法及其向人类疾病转化方面的效用。由于症状性疼痛的治疗很重要，本综述强调了小鼠中关键的疼痛样行为评估，并探讨了与椎间盘源性背痛相关的当前行为评估。总体而言，确定具体的研究问题对于识别相关模型至关重要，其中组织学染色、成像、细胞外基质组成、力学和疼痛是评估退变和再生策略的关键参数。
