Diet-induced obesity leads to behavioral indicators of pain preceding structural joint damage in wild-type mice

Geoffrey J. Kerr,Matthew W. Grol,Bethia To,Ian White,Cheryle A. Séguin,Frank Beier,Magali Millecamps,Laura S. Stone

doi:10.1186/s13075-021-02463-5

Geoffrey J. Kerr, Matthew W. Grol + Show 6 more

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https://doi.org/10.1186/s13075-021-02463-5

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Abstract

IntroductionObesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Despite the clinical association, no studies have directly assessed whether diet-induced obesity accelerates IVD degeneration, back pain, or investigated the biological mediators underlying this association. In this study, we examine the effects of chronic consumption of a high-fat or high-fat/high-sugar (western) diet on the IVD, knee joint, and pain-associated outcomes.MethodsMale C57BL/6N mice were randomized into one of three diet groups (chow control; high-fat; high-fat, high-sugar western diet) at 10 weeks of age and remained on the diet for 12, 24, or 40 weeks. At endpoint, animals were assessed for behavioral indicators of pain, joint tissues were collected for histological and molecular analysis, serum was collected to assess for markers of systemic inflammation, and IBA-1, GFAP, and CGRP were measured in spinal cords by immunohistochemistry.ResultsAnimals fed obesogenic (high-fat or western) diets showed behavioral indicators of pain beginning at 12 weeks and persisting up to 40 weeks of diet consumption. Histological indicators of moderate joint degeneration were detected in the IVD and knee following 40 weeks on the experimental diets. Mice fed the obesogenic diets showed synovitis, increased intradiscal expression of inflammatory cytokines and circulating levels of MCP-1 compared to control. Linear regression modeling demonstrated that age and diet were both significant predictors of most pain-related behavioral outcomes, but not histopathological joint degeneration. Synovitis was associated with alterations in spontaneous activity.ConclusionDiet-induced obesity accelerates IVD degeneration and knee OA in mice; however, pain-related behaviors precede and are independent of histopathological structural damage. These findings contribute to understanding the source of obesity-related back pain and the contribution of structural IVD degeneration.

Highlights

Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain
This analysis showed a significant increase in overall bone mineral density (BMD) in mice fed the high-fat diet at all timepoints, and at the 24- and 40-week timepoints for mice fed the western diet, compared to age-matched chow-fed controls (Fig. 1c)
Grip force during axial stretch was reduced in mice fed the high-fat diet compared to age-matched chow-fed controls at 12 and 40 weeks and in mice fed the western diet at all time points compared to control (Fig. 2c), suggesting decreased tolerance to axial stretch

Summary

Introduction

Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Obesity substantially increases the risk of developing metabolic, cardiovascular, neurological, and musculoskeletal diseases [1], and with the prevalence nearly tripling over the last 30 years [1], it poses a large public health concern Obesity decreases both life expectancy [2] and quality of life and is associated with increased disability, mental illness, and unemployment [1, 3]. Despite efforts to improve the clinical management of LBP, treatments are largely limited to symptomatic relief, often without treating the underlying cause of the pain [7]. This is largely due to an incomplete understanding of the tissues and pathways involved in the initiation and progression of LBP. While several tissues appear to be involved in LBP, including the paraspinal muscles, ligaments, and facet joints [8,9,10], degeneration of the fibrocartilaginous intervertebral disc (IVD) is believed to be the major contributor to pain in an approximately 40% of cases [8]

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