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

Abstract

Introduction Obesity 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. Methods Male 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. Results Animals 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. Conclusion Diet-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.

The cGAS-STING Pathway Affects Vertebral Bone but Does Not Promote Intervertebral Disc Cell Senescence or Degeneration

“…The findings in the disc do however align with the recent work of Gorth et al in hTNF-α overexpression mouse models and contribute to a growing body of evidence demonstrating the marginal impacts of systemic inflammation on overall disc health ( 30 , 62 ). Other in vivo models of systemic inflammation, including high fat diet-induced obesity, have shown disc and articular cartilage architecture are not negatively impacted by systemic inflammatory conditions ( 63 , 64 ). This can likely be attributed to the lack of vasculature in both tissues.…”

Comparative histopathological analysis of age‐associated intervertebral disc degeneration in CD‐1 and C57BL/6 mice: Anatomical and sex‐based differences

“…Here, we report a detailed histopathological characterization of age‐associated IVD degeneration in both male and female C57BL/6 and CD‐1 mice. These mouse strains were specifically selected as they are commonly used for the generation of transgenic strains and/or in studies of IVD development, injury, and degeneration 23,28,30–34 . In keeping with previous studies, 28 C57BL/6 mice displayed only mild IVD degeneration until 24 months of age; at this point, the lumbar spine demonstrated the most degeneration compared to other regions.…”

Inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet

“…Multiple studies have shown that an experimental high-fat diet (HFD) leads to chronic, low-grade systemic inflammation and progressive dysfunction of multiple organs and tissues. HFD causes osteoarthritis (OA) in mice (19,20), sarcopenia, osteoporosis, and multiple organ dysfunction, including endocrine organs, liver, kidney, and cardiac (reviewed in (21)). HFD also leads to a significant elevation of IL-6, MCP-1, and CRP levels in the systemic circulation (21)(22)(23).…”