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Simvastatin Inhibits IL-1β-Induced Apoptosis and Extracellular Matrix Degradation by Suppressing the NF-kB and MAPK Pathways in Nucleus Pulposus Cells

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Abstract

Statins are widely used hypocholesterolemic drugs that block the mevalonate pathway. Some studies have shown that statins may have the potential to inhibit intervertebral disk (IVD) degeneration (IDD). Interleukin (IL)-1β, a catabolic cytokine, is a key regulator of IDD. This study aimed to investigate the mechanism underlying the effect of simvastatin on IDD. The viability of nucleus pulposus (NP) cells was determined by the methyl-thiazolyl-tetrazolium (MTT) assay. The apoptosis of NP cells was measured by flow cytometric analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and western blotting of relevant apoptotic proteins. The protein levels of catabolic factors and anabolic factors were determined by western blotting. The cells were stimulated with IL-1β in the absence or presence of simvastatin to investigate the effects on matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, type II collagen, and aggrecan expression. Our findings indicate that simvastatin considerably inhibited IL-1β-induced apoptosis in NP cells. We also found that simvastatin attenuated IL-1β-induced expression and MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 activities and also reduced the decrease in type II collagen and aggrecan expression. In addition, simvastatin considerably suppressed the nuclear translocation and activation of nuclear factor-kappa B (NF-KB) by inhibiting p65 phosphorylation and translocation and blocking inhibitor kB-α degradation. It also inhibited MAPK pathway activation by blocking c-Jun N-terminal kinase (JNK), p38, and ERK phosphorylation. The results of our study revealed that simvastatin is a potential agent for IDD prevention and treatment.

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Acknowledgments

This study was funded by grant from the National Natural Science Foundation of China (grant numbers, 81072187, 81541056).

Author Contributions

J.T. designed the study and drafted the manuscript. W.L. participated in designing the study and carried the molecular mechanism studies and immunoassays. Y.Z. and X.W. revised the manuscript. Y.S., L.K., W.L., and K.W. participated in collecting clinical samples. S.L. and W.H. did the statistical analysis. C.Y. conceived the study and helped revise the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road, No. 1277, Wuhan, 430022, People’s Republic of China

    Ji Tu, Yukun Zhang, Xinghuo Wu, Yu Song, Liang Kang, Wei Liu, Kun Wang, Shuai Li, Wenbin Hua & Cao Yang

  2. Wuhan Institute of Biological Products Co., Ltd., 430207, Wuhan, Hubei, People’s Republic of China

    Wentian Li

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  1. Ji Tu
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Correspondence to Cao Yang.

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Tu, J., Li, W., Zhang, Y. et al. Simvastatin Inhibits IL-1β-Induced Apoptosis and Extracellular Matrix Degradation by Suppressing the NF-kB and MAPK Pathways in Nucleus Pulposus Cells. Inflammation 40, 725–734 (2017). https://doi.org/10.1007/s10753-017-0516-6

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