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.

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 and pain-associated outcomes. Methods: Male C57BL/6N mice were randomized into one of three diet groups (control chow; 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, 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 joint degeneration were not detected in the IVD or knee until 40 weeks on the experimental diets. Mice fed the obesogenic diets showed 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.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.

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nuclear genome but different mtDNA variants (named conplastic mice) during aging and forced exercise. Methods: Conplastic mice (BL/6 NZB) strain was developed with the C57BL/6JOlaHsd nuclear genome and the NZB/OlaHsd mtDNA to compare with the original C57BL/6JOlaHsd strain (BL/6 C57 ). Knee joints from BL/6 NZB mice as well as from BL/6 C57 mice were processed and cut into coronal sections. The mice were sacrificed at 25, 75 and 90 weeks of age and knee joints were collected for histological analysis. All sections were stained with Hematoxylin-Eosine and Safranin O-fast green and graded using a Mankin scoring system. All quadrants of the joint (medial tibial plateau, medial femoral condyle, lateral tibial plateau, and lateral femoral condyle) were scored separately and averaged. Three criteria were selected for histological assessment of each quadrant: structure, cellularity and matrix staining. Another group of mice from both BL/6 NZB and BL/6 C57 strains were subjected to exercise by running in a treadmill 400m/day three times a week. After 75 and 90 weeks of age, mice were sacrificed and knee joints were processed for histological analysis. Cartilage expression of markers of autophagy like LC3 and metalloproteinases like MMP-13 were also analyzed by immunohistochemistry in both strains. The results are given as mean ± SEM and statistical analysis was performed using non parametric unpaired t-test (Graph Pad Prism v 6.0). Results: In response to aging, conplastic mice BL/6 NZB presented reduced cartilage Mankin score at 25 (p¼0.0079), 75 (p¼0.0087) and 90 (p¼0.064) weeks when compared with mice of the original strain BL/ 6 C57 at the same age. Specifically, we showed a reduced score in both femoral condyle (FC) and tibial plateau (TP) of BL/6 NZB mice that reached the statistical significance at 25 (FC: p¼0.0317; TP: p¼0.0079), 75 (FC: p¼0.0411; TP: p¼0.0238) and borderline the statistical significance at 90 (FC: p¼0.0649; TP: p¼0.0628) weeks of age. These results were accompanied with more expression of LC3 in cartilage from BL/6 NZB mice at 75 weeks when compared with cartilage from BL/ 6 C57 at the same age (p¼0.0152). We also reported a significant decrease of LC3 expression in cartilage from mice at 75 weeks when compared with mice at 25 weeks in both strains confirming the decrease of autophagy with aging. Difference in MMP13 cartilage expression between the two mice strains were also found. In the mice subjected to exercise, BL/6 C57 presented an increased cartilage score in the medial compartment (p¼0.0286) and lateral compartment (p¼0.057) of the joint at 90 weeks when compared with BL/6 NZB mice at the same age.Conclusions: This study demonstrated that aging and forced exercise in conplastic mice BL/6 NZB are associated with a reduced joint deterioration compared with the original strain BL/6 C57 . Moreover, we showed that mtDNA variants can improve the aging process at joint level through the modulation of autophagy. These results support the hypothesis that mtDNA background has a role in the process...

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