In vivo Mouse Intervertebral Disc Degeneration Models and Their Utility as Translational Models of Clinical Discogenic Back Pain: A Comparative Review

Abstract

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 in vitro 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 in vivo 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.

Three-dimensional culture model to study the biology of vacuolated notochordal cells from mouse nucleus pulposus explants

“…Moreover, many studies report the generation of NC-or NP-conditional knockouts for the study of IVD homeostasis, progressing the research on the human disease. In this context, the current model is worthy of interest for studies at the cellular and molecular levels of the phenotypic changes in mature NCs isolated from genetically engineered mice (Tang et al, 2022).…”

“…These vacuoles are gradually lost during NP growth and maturation. In ageing mice, cells within the NP become vacuole-free NPCs (Mohanty et al, 2019;Tam et al, 2018).…”

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

“…Animal models have been proven to be essential tools for understanding disease mechanisms and detecting potential treatment methods of DLBP. Ranging from large to small animals, single or multiple-level mechanical lumbar disc injury models have been developed through ventral, dorsal, or lateral punctures approaches using needles or surgical blades ( Millecamps and Stone, 2018 ; Shi et al, 2018b ; Tang et al, 2022 ). We used a previously reported mouse DLBP model in this study, which was set up by puncture and removal of part of the lumbar nucleus pulposus ( Shi et al, 2018a ).…”

Controversies in spine research: Organ culture versus in vivo models for studies of the intervertebral disc

“…Evaluation of pain as an outcome measure in studying therapeutics for IVDD is critical. While in vivo models may be useful for studying behavioral characteristics, the translatability of pain behaviors assessed in animal models, especially small rodents, to the human condition requires further validation 111 . Furthermore, the induction of IVDD using AF puncture in animal models does not necessarily recapitulate the initiating mechanisms of IVDD in humans.…”

“…While in vivo models may be useful for studying behavioral characteristics, the translatability of pain behaviors assessed in animal models, especially small rodents, to the human condition requires further validation. 111 Furthermore, the induction of IVDD using AF puncture in animal models does not necessarily recapitulate the initiating mechanisms of IVDD in humans. Nevertheless, there are many similarities in the degenerative changes in IVD structure and chronicity of inflammatory and pain‐associated cytokines.…”