Alarmins S100A8/A9 promote intervertebral disc degeneration and inflammation-related pain in a rat model through toll-like receptor-4 and activation of the NF-κB signaling pathway

Zheng, Jinjian; Wang, Jianru; Liu, Hui; Chen, Fan; Wang, Hua; Chen, Shunlun; Xie, Jiahua; Zheng, Zhaomin; Li, Zemin

doi:10.1016/j.joca.2022.03.011

Cited by 20 publications

(15 citation statements)

References 44 publications

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“… 43 , 44 , 45 Zheng et al. 46 reported that S100A8/A9 binds to TLR4 to increase the expression of MMPs, TNF‐α, and IL‐6 in NP cells through the NF‐κB signalling pathway, delaying the IVDD progression. Similarly, Zou et al.…”

Section: Discussionmentioning

confidence: 99%

“…The NF-κB pathway is considered an important signalling pathway within cells primarily because it can regulate various pathophysiological processes such as cell inflammation,apoptosis, ECM degradation and aging [43][44][45]. Zheng et al46 reported that S100A8/A9 binds to TLR4 to increase the expression of MMPs, TNF-α, and IL-6 in NP cells through the NF-κB signalling pathway, delaying the IVDD progression. Similarly, Zou et al47 found that HO-1 expression was lower in the NP cells of patients with IVDD than in that of those in the early IVDD group.…”

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confidence: 99%

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DNMT3a‐mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF‐κB pathway

Cheng,

Wei,

Chen

et al. 2023

J Cellular Molecular Medi

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Intervertebral disc degeneration (IVDD) is a common chronic musculoskeletal disease that causes chronic low back pain and imposes an immense financial strain on patients. The pathological mechanisms underlying IVDD have not been fully elucidated. The development of IVDD is closely associated with abnormal epigenetic changes, suggesting that IVDD progression may be controlled by epigenetic mechanisms. Consequently, this study aimed to investigate the role of epigenetic regulation, including DNA methyltransferase 3a (DNMT3a)‐mediated methylation and peroxisome proliferator‐activated receptor γ (PPARγ) inhibition, in IVDD development. The expression of DNMT3a and PPARγ in early and late IVDD of nucleus pulposus (NP) tissues was detected using immunohistochemistry and western blotting analyses. Cellularly, DNMT3a inhibition significantly inhibited IL‐1β‐induced apoptosis and extracellular matrix (ECM) degradation in rat NP cells. Pretreatment with T0070907, a specific inhibitor of PPARγ, significantly reversed the anti‐apoptotic and ECM degradation effects of DNMT3a inhibition. Mechanistically, DNMT3a modified PPARγ promoter hypermethylation to activate the nuclear factor‐κB (NF‐κB) pathway. DNMT3a inhibition alleviated IVDD progression. Conclusively, the results of this study show that DNMT3a activates the NF‐κB pathway by modifying PPARγ promoter hypermethylation to promote apoptosis and ECM degradation. Therefore, we believe that the ability of DNMT3a to mediate the PPARγ/NF‐κB axis may provide new ideas for the potential pathogenesis of IVDD and may become an attractive target for the treatment of IVDD.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

DNMT3a‐mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF‐κB pathway

Cheng,

Wei,

Chen

et al. 2023

J Cellular Molecular Medi

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“…The role of RLN1 has not been demonstrated in IDD up to now, but Jin et al predicted it as an immune-related biomarker of sciatica, which also falls within the category of IDD [ 36 ]. The calcium-binding protein S100A9 has been shown to induce nucleus cell apoptosis through the activation of the NF-B signaling pathway, cause matrix degradation and amplify inflammation, and can be used as a biomarker for IDD [ 37 , 38 ]. However, S100Z, affiliated with the same family, has not been mentioned in the progression of IDD.…”

Section: Discussionmentioning

confidence: 99%

Significance of Immune-Related Genes in the Diagnosis and Classification of Intervertebral Disc Degeneration

Huang

Zhang

et al. 2022

Journal of Immunology Research

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Background. With the extensive development of intervertebral disc degeneration (IDD) research, IDD has been found to be a complex disease associated with immune-related gene (IRGs) changes. Nonetheless, the roles of IRGs in IDD are unclear. Methods. In our study, 11 IRGs were chosen using differential analysis between nondisc degeneration and degenerative patients from the GEO database. Then, we utilized a random forest (RF) model to screen six candidate IRGs to predict the risk of IDD. A nomogram was developed on the basis of six candidate IRGs, and DCA showed that patients could benefit from the nomogram. Based on the selected significant IRGs, a consensus clustering approach was used to differentiate disc degeneration patients into two immune patterns (immune cluster A and B). The PCA algorithm was constructed to compute immune scores for every sample, to quantify immune patterns. The immune scores of immune cluster B patients were higher than those of immune cluster A. Results. Through differential expression analysis between healthy and IDD samples, 11 significant IRGs (CTSS, S100Z, STAT3, KLRK1, FPR1, C5AR2, RLN1, IFGR2, IL2RB, IL17RA, and IL6R) were recognized through significant IRGs. The “Reverse Cumulative Distribution of Residual” and “Boxplots of Residual” indicate that the RF model has minimal residuals. The majority of samples in the model have relatively small residuals, demonstrating that the model is better. Besides, the nomogram model was constructed based on importance and the IRGs with importance scores greater than 2 (FPR1, RLN1, S100Z, IFNGR2, KLRK1, and CTSS). The nomogram model revealed that decision-making based on an established model might be beneficial for IDD patients, and the predictive power of the nomogram model was significant. In addition, we identified two different immune cluster patterns (immune cluster A and immune cluster B) based on the 11 IRGs. We found that immune cluster A had significantly higher levels of MDSC, neutrophil, plasmacytoid dendritic cell, and type 17 T helper cell expression than immune cluster B. And we calculated the score for each sample to quantify the gene patterns. The patients in immune cluster B or gene cluster B had higher immune scores than those in immune cluster A or gene cluster A. Conclusion. In conclusion, IRGs play an extremely significant role in the occurrence of IDD. Our study of immune patterns may guide the strategies of prevention and treatment for IDD in the future.

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“…Recently, Wang et al that Fer-1, which is an inhibitor of iron death, could downregulate TLR4 expression and thus inhibit the NF-KB pathway to alleviate IVDD in rats ( 55 ). In addition, Zheng et al showed that the protein S100A8/A9 exacerbated IVDD by binding to TLR4 and activating the NF-KB signaling pathway to upregulate the expression of matrix metalloproteinases, TNF-α and IL-6 ( 56 ). Moreover, TLR4 is closely associated with the NLRP3 inflammasome.…”

Section: Immunomodulation Associated With Ivddmentioning

confidence: 99%

Current status and development direction of immunomodulatory therapy for intervertebral disk degeneration

Gao,

Chen,

Zheng

et al. 2023

Front. Med.

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Intervertebral disk (IVD) degeneration (IVDD) is a main factor in lower back pain, and immunomodulation plays a vital role in disease progression. The IVD is an immune privileged organ, and immunosuppressive molecules in tissues reduce immune cell (mainly monocytes/macrophages and mast cells) infiltration, and these cells can release proinflammatory cytokines and chemokines, disrupting the IVD microenvironment and leading to disease progression. Improving the inflammatory microenvironment in the IVD through immunomodulation during IVDD may be a promising therapeutic strategy. This article reviews the normal physiology of the IVD and its degenerative mechanisms, focusing on IVDD-related immunomodulation, including innate immune responses involving Toll-like receptors, NOD-like receptors and the complement system and adaptive immune responses that regulate cellular and humoral immunity, as well as IVDD-associated immunomodulatory therapies, which mainly include mesenchymal stem cell therapies, small molecule therapies, growth factor therapies, scaffolds, and gene therapy, to provide new strategies for the treatment of IVDD.

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Alarmins S100A8/A9 promote intervertebral disc degeneration and inflammation-related pain in a rat model through toll-like receptor-4 and activation of the NF-κB signaling pathway

Cited by 20 publications

References 44 publications

DNMT3a‐mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF‐κB pathway

DNMT3a‐mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF‐κB pathway

Significance of Immune-Related Genes in the Diagnosis and Classification of Intervertebral Disc Degeneration

Current status and development direction of immunomodulatory therapy for intervertebral disk degeneration

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