Dataset Information

17beta-estradiol Attenuates TNF-α-Induced Premature Senescence of Nucleus Pulposus Cells through Regulating the ROS/NF-κB Pathway.

ABSTRACT:

Background

Accelerated cellular senescence within the nucleus pulposus (NP) region is a common feature of disc degeneration. Our previous work indicated that TNF-α promoted NP cell senescence. Although the intervertebral disc has been reported to be an estrogen-sensitive tissue, it is unclear whether estrogen can inhibit premature senescence of NP cells.

Objective

To investigate whether 17beta-estradiol (E₂) can attenuate TNF-α-induced premature senescence of NP cells and the potential mechanism behind this regulatory process.

Methods

Isolated NP cells and intact intervertebral discs from healthy rats were cultured with or without TNF-α, E₂ or their combination. The pan estrogen receptor (ER) antagonist ICI 182780 was used to investigate the role of ER. Direct and indirect indicators including cell proliferation, SA-β-Gal activity, telomerase activity, cell cycle, and the expression of matrix macromolecules (aggrecan and collagen II) and senescence markers (p16 and p53) were used to evaluate the premature senescence of NP cells. Additionally, intracellular reactive oxygen species (ROS) and NF-κB/p65 activity were also detected in the NP cell cultures.

Results

In the NP cell cultures, E₂ significantly increased cell proliferation potency, telomerase activity and the expression of matrix macromolecules but attenuated SA-β-Gal activity, senescence marker (p53 and p16) expression and G1 cycle arrest in TNF-α-treated NP cells. Furthermore, E₂ inhibited ROS generation and phospho-NF-κB/p65 expression in the TNF-α-treated NP cells. However, the ER antagonist ICI 182780 abolished the effects of E₂ on TNF-α-treated NP cells. In the disc organ cultures, E₂ also significantly increased matrix synthesis, whereas it decreased senescence marker (p53 and p16) expression, which could be abolished by the ER antagonist ICI 182780.

Conclusion

The interaction between E₂ and ER can attenuate TNF-α-induced premature senescence of rat NP cells through interfering with the ROS/NF-κB pathway.

SUBMITTER: Li P

PROVIDER: S-EPMC5332869 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

17beta-estradiol Attenuates TNF-α-Induced Premature Senescence of Nucleus Pulposus Cells through Regulating the ROS/NF-κB Pathway.

Li Pei P Gan Yibo Y Xu Yuan Y Wang Liyuan L Ouyang Bin B Zhang Chengmin C Luo Lei L Zhao Chen C Zhou Qiang Q

International journal of biological sciences 20170115 2

<h4>Background</h4>Accelerated cellular senescence within the nucleus pulposus (NP) region is a common feature of disc degeneration. Our previous work indicated that TNF-α promoted NP cell senescence. Although the intervertebral disc has been reported to be an estrogen-sensitive tissue, it is unclear whether estrogen can inhibit premature senescence of NP cells.<h4>Objective</h4>To investigate whether 17beta-estradiol (E<sub>2</sub>) can attenuate TNF-α-induced premature senescence of NP cells a ...[more]

PMID: 28255267

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Project description:Luteolin (3',4',5,7-tetrahydroxy flavone) is a flavonoid, which is widely distributed in various plants including flowers, vegetables, and medicinal herbs and spices. Luteolin can be applied in the treatment of various diseases due to its multiple biological activities, such as anti-inflammatory, anticancer, and antioxidative activity. However, its role in intervertebral disc degeneration has not been previously reported. Therefore, the purpose of the present study was to explore the effects of luteolin on Tumor necrosis factor (TNF)-α-induced inflammatory injury and senescence of human nucleus pulposus cells (HNPCs), as well as the underlying mechanisms of action of this compound. Cell viability and apoptosis were assessed by MTT assay and TUNEL staining, respectively. ELISA kits were applied to detect the levels of inflammatory cytokines and the activity of telomerase. Senescence β-galactosidase staining was used to detect the activity levels of β-galactosidase in the cells. Cell transfection was performed to achieve interference of sirtuin 6 (Sirt6). The protein expression levels were detected by western blot analysis. TUNEL staining and western blot analysis were performed to assess the expression levels of apoptosis-related proteins. The results indicated that TNF-α induced a significant decrease in HNPC viability and an increase in inflammatory factor levels, while the application of luteolin effectively increased cell viability and decreased intracellular interleukin (IL)-1β and IL-6 expression levels. Furthermore, luteolin decreased apoptosis compared with the TNF-α groups in a dose-dependent manner. In addition, the results of the detection kits suggested that luteolin reversed TNF-α-induced senescence. Notably, interference with Sirt6 partially reduced the protective effect of luteolin on TNF-α-induced HNPC senescence via the Sirt6/NF-κB pathway. In summary, the data indicated that luteolin suppresses TNF-α-induced inflammatory injury and senescence of HNPCs via the Sirt6/NF-κB pathway.

Project description:Intervertebral disc (IVD) degeneration (IVDD) which is highly prevalent within the elderly population, is a leading cause of chronic low back pain and disability. Nucleus pulposus (NP) cell senescence plays an indispensable role in the pathogenesis of IVDD. Morroniside is a major iridoid glycoside and one of the quality control metrics of Cornus officinalis Siebold & Zucc (CO). An increasing body of evidence suggests that morroniside and CO-containing formulae share many similar biological effects, including anti-inflammatory, anti-oxidative, and anti-apoptotic properties. In a previous study, we reported that Liuwei Dihuang Decoction, a CO-containing formula, is effective for treating IVDD by targeting p53 expression; however, the therapeutic role of morroniside on IVDD remains obscure. In this study, we assessed the pharmacological effects of morroniside on NP cell senescence and IVDD pathogenesis using a lumbar spine instability surgery-induced mouse IVDD model and an in vitro H2O2-induced NP cell senescence model. Our results demonstrated that morroniside administration could significantly ameliorate mouse IVDD progression, concomitant with substantial improvement in extracellular matrix metabolism and histological grading score. Importantly, in vivo and in vitro experiments revealed that morroniside could significantly reduce the increase in SA-β-gal activities and the expression of p53 and p21, which are the most widely used indicators of senescence. Mechanistically, morroniside suppressed ROS-induced aberrant activation of Hippo signaling by inhibiting Mst1/2 and Lats1/2 phosphorylation and reversing Yap/Taz reduction, whereas blockade of Hippo signaling by Yap/Taz inhibitor-1 or Yap/Taz siRNAs could antagonize the anti-senescence effect of morroniside on H2O2-induced NP cell senescence model by increasing p53 expression and activity. Moreover, the inhibition of Hippo signaling in the IVD tissues by morroniside was further verified in mouse IVDD model. Taken together, our findings suggest that morroniside protects against NP cell senescence to alleviate IVDD progression by inhibiting the ROS-Hippo-p53 pathway, providing a potential novel therapeutic approach for IVDD.

Dataset Information

17beta-estradiol Attenuates TNF-α-Induced Premature Senescence of Nucleus Pulposus Cells through Regulating the ROS/NF-κB Pathway.

Background

Objective

Methods

Results

Conclusion

Publications

17beta-estradiol Attenuates TNF-α-Induced Premature Senescence of Nucleus Pulposus Cells through Regulating the ROS/NF-κB Pathway.

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