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 and… Show more
“…One study evaluated pain behaviors and joint damage in the context of diet-induced obesity. This study reported obesity from a high-fat or Western diet (HFD) resulted in pain behaviors (increased mechanical sensitivity and altered spontaneous locomotion) in 24-week and 40-week old mice compared to 12-week old mice, and these behaviors preceded joint damage (61). Though the authors did not statistically report difference between age groups (only between different diet groups), if one looks at the chow-fed mice from 12-weeks to 40-weeks of age there is a decrease in spontaneous locomotion and increase in osteophytes in these aged mice, which is consistent with our findings.…”
Objective: Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. While injury-induced OA models are useful, only a subset of OA is linked to traumatic injury. Here, we aimed to characterize age-associated joint damage, mechanical sensitization, and dorsal root ganglia (DRG) immune phenotypes in mice of both sexes.
Methods: Male or female mice aged 6- or 20-months old were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 dorsal root ganglia (DRG) immune characterization via flow cytometry. DRG gene expression in aged mice and humans was also examined.
Results: Twenty-month old male mice had worse cartilage degeneration than 6-month old mice. Older female knees showed increased cartilage degeneration, but to a lesser degree than males. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells, and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male DRGs showed increased expression of Ccl2 and Ccl5 and older female DRGs showed increased Cxcr4 and Ccl3 compared to 6-month DRGs, among other differentially expresssed genes. Human DRG analysis from six individuals >80 years old revealed elevated CCL2 in male DRGs compared to females, whereas CCL3 was higher in female DRGs.
Conclusions: Here we show that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of analgesic therapies.
“…One study evaluated pain behaviors and joint damage in the context of diet-induced obesity. This study reported obesity from a high-fat or Western diet (HFD) resulted in pain behaviors (increased mechanical sensitivity and altered spontaneous locomotion) in 24-week and 40-week old mice compared to 12-week old mice, and these behaviors preceded joint damage (61). Though the authors did not statistically report difference between age groups (only between different diet groups), if one looks at the chow-fed mice from 12-weeks to 40-weeks of age there is a decrease in spontaneous locomotion and increase in osteophytes in these aged mice, which is consistent with our findings.…”
Objective: Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. While injury-induced OA models are useful, only a subset of OA is linked to traumatic injury. Here, we aimed to characterize age-associated joint damage, mechanical sensitization, and dorsal root ganglia (DRG) immune phenotypes in mice of both sexes.
Methods: Male or female mice aged 6- or 20-months old were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 dorsal root ganglia (DRG) immune characterization via flow cytometry. DRG gene expression in aged mice and humans was also examined.
Results: Twenty-month old male mice had worse cartilage degeneration than 6-month old mice. Older female knees showed increased cartilage degeneration, but to a lesser degree than males. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells, and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male DRGs showed increased expression of Ccl2 and Ccl5 and older female DRGs showed increased Cxcr4 and Ccl3 compared to 6-month DRGs, among other differentially expresssed genes. Human DRG analysis from six individuals >80 years old revealed elevated CCL2 in male DRGs compared to females, whereas CCL3 was higher in female DRGs.
Conclusions: Here we show that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of analgesic therapies.
“…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 (30,61). Other in vivo models of systemic inflammation, including high fat diet-induced obesity, have shown disc architecture is not negatively impacted by inflammatory conditions that are not local (62,63). As seen in the structurally intact discs of these models, N153S NP tissues retained healthy, vacuolated cells expressing the NP-phenotypic marker CA3 and an aggrecan-rich matrix.…”
The DNA-sensing cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) and mediates type-I interferon inflammatory responses to foreign viral and bacterial DNA as well as self-DNA. Studies of the intervertebral disc in humans and mice demonstrate associations between aging, increased cell senescence, and disc degeneration. Herein we assessed the role of STING in SASP promotion in STING gain- (N153S) and loss-of-function mouse models. N153S mice evidenced elevated circulating levels of proinflammatory markers including IL-1b, IL-6, and TNF-a and exhibited a mild trabecular and cortical bone phenotype in caudal vertebrae. Interestingly, despite systemic inflammation, the structural integrity of the disc and knee articular joint remained intact, and cells did not show a loss of their phenotype or elevated SASP. Transcriptomic analysis of N153S tissues demonstrated an upregulated immune response by disc cells, which did not closely resemble inflammatory changes in human tissues. Interestingly, STING-/- mice also showed a mild vertebral bone phenotype, but the absence of STING did not improve the age-associated disc phenotype or reduce the abundance of SASP markers. Overall, the analyses of N153S and STING-/- mice that the cGAS-STING pathway is not a major contributor to SASP induction and consequent disc aging and degeneration but may play a minor role in the maintenance of trabecular bone in the vertebrae. This work contributes to a growing body of work demonstrating that systemic inflammation is not a key driver of disc degeneration.
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