Dehydrocostus Lactone Attenuates the Senescence of Nucleus Pulposus Cells and Ameliorates Intervertebral Disc Degeneration via Inhibition of STING-TBK1/NF-κB and MAPK Signaling.

Zhiqian Chen,Kai Zhang,Jie Zhao,Chen Chen,Xiao Yang,Yifan Zhou,Tangjun Zhou,Zhihao Liang,Xiankun Cao,Chen Han,An Qin,Wenxin He

doi:10.3389/fphar.2021.641098

Abstract

The progression of intervertebral disc degeneration (IDD) is multifactorial with the senescence of nucleus pulposus (NP) cells and closely related to inflammation in NP cells. Dehydrocostus lactone (DHE) is a natural sesquiterpene lactone isolated from medicinal plants that has anti-inflammatory properties. Thus, DHE may have a therapeutic effect on the progression of IDD. In this study, NP cells were used to determine the appropriate concentration of DHE in vitro. The role of DHE in tumor necrosis factor-α (TNF-α)–induced activation of inflammatory signaling pathways and cellular senescence, together with anabolism and catabolism of extracellular matrix (ECM) in NP cells, was examined in vitro. The therapeutic effect of DHE in vivo was determined using a spinal instability model of IDD in mice. The TNF-α–induced ECM degradation and the senescence of NP cells were partially attenuated by DHE. Mechanistically, DHE inhibited the activation of NF-κB and MAPK inflammatory signaling pathways and ameliorated the senescence of NP cells caused by the activation of STING-TBK1/NF-κB signaling induced by TNF-α. Furthermore, a spinal instability model in mice demonstrated that DHE treatment could ameliorate progression of IDD. Together, our findings indicate that DHE can alleviate IDD changes and has a potential therapeutic function for the treatment of IDD.

Highlights

Lumbar intervertebral disc degeneration (IDD) is the major underlying cause of low back pain (D’Silva et al, 2019) and usually precedes other spinal degenerative disorders, including lumbar disc herniation and spinal stenosis, which result in a significant economic burden and enormous influences on quality of life (Safiri et al, 2020)
Cell senescence and inflammatory response lead to the catabolic upregulation of nucleus pulposus (NP) cells, which results in the imbalance of extracellular matrix (ECM) metabolism and, causes ECM degradation
Immunoblotting showed the decreased expression level of stimulator of interferon genes (STING) and the increased phosphorylation of TBK1 after treatment with tumor necrosis factor-α (TNF-α) for 4 or 8 h. This phenomenon was ameliorated by treatment with Dehydrocostus lactone (DHE) (Figure 3E and Supplementary Figure 4A). These findings suggest that the activation of the NF-κB and mitogen-activated protein kinase (MAPK) pathways and the cellular senescence–related double-stranded DNA (dsDNA)-STING signaling that is induced by TNF-α could be inhibited by DHE

Summary

Introduction

Lumbar intervertebral disc degeneration (IDD) is the major underlying cause of low back pain (D’Silva et al, 2019) and usually precedes other spinal degenerative disorders, including lumbar disc herniation and spinal stenosis, which result in a significant economic burden and enormous influences on quality of life (Safiri et al, 2020). NP cell senescence, inflammation, and ECM degradation are considered the main molecular mechanisms of IDD (Feng et al, 2016; Zhang et al, 2016). Tumor necrosis factor-α (TNF-α) is the key inflammatory factor that accelerates senescence of NP cells and induces the expression of other inflammatory mediators (Postal and Appenzeller, 2011; Johnson et al, 2015; Khan et al, 2017); as a result, matrix metalloproteinase (MMP) increases and, loss of ECM occurs and IDD develops (Sun et al, 2015). Effective inhibition of TNF-α, of TNFα–induced NP cell senescence, and of inflammatory mediators may treat IDD

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