Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation

Zhao, Yunpeng; Qiu, Cheng; Wang, Wenhan; Peng, Jiangfan; Cheng, Xiang; Shangguan, Yangtao; Xu, Mingyang; Li, Jiayi; Qu, Ruize; Chen, Xiaomin; Jia, Suyi; Luo, Dan; Liu, Long; Li, Peng; Guo, Fengjin; Vasilev, Krasimir; Liu, Liang; Hayball, John; Dong, Shuli; Pan, Xin; Li, Yuhua; Guo, Linlin; Cheng, Lei; Li, Weiwei

doi:10.7150/thno.45359

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Theranostics 2020; 10(15):7015-7033. doi:10.7150/thno.45359 This issue Cite

Research Paper

Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation

Yunpeng Zhao^1*, Cheng Qiu^1,2*, Wenhan Wang^1,2, Jiangfan Peng², Xiang Cheng², Yangtao Shangguan², Mingyang Xu², Jiayi Li², Ruize Qu^1,2, Xiaomin Chen^1,2, Suyi Jia², Dan Luo³, Long Liu⁴, Peng Li⁴, Fengjin Guo⁵, Krasimir Vasilev^6,7, Liang Liu⁸, John Hayball^8,9, Shuli Dong¹⁰, Xin Pan¹, Yuhua Li¹, Linlin Guo², Lei Cheng^1✉, Weiwei Li^4✉

1. Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
2. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
3. College of Stomatology, Qingdao University, Qingdao, Shandong, 266071, P. R. China.
4. Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
5. Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing, 400016, P. R. China.
6. Future Industries Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia.
7. School of Engineering, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia.
8. Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Adelaide SA 5000, Australia.
9. Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia.
10. Key Laboratory of Colloid and Interface Chemistry (Shandong University), Ministry of Education, Jinan, 250100, P. R. China.
*These authors contributed equally to this work.

Citation:

Zhao Y, Qiu C, Wang W, Peng J, Cheng X, Shangguan Y, Xu M, Li J, Qu R, Chen X, Jia S, Luo D, Liu L, Li P, Guo F, Vasilev K, Liu L, Hayball J, Dong S, Pan X, Li Y, Guo L, Cheng L, Li W. Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics 2020; 10(15):7015-7033. doi:10.7150/thno.45359. https://www.thno.org/v10p7015.htm

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Abstract

Background: Intervertebral disc (IVD) degeneration is a common degenerative disease that can lead to collapse or herniation of the nucleus pulposus (NP) and result in radiculopathy in patients.

Methods: NP tissue and cells were isolated from patients and mice, and the expression profile of cortistatin (CST) was analysed. In addition, ageing of the NP was compared between 6-month-old WT and CST-knockout (CST^-/-) mice. Furthermore, NP tissues and cells were cultured to validate the role of CST in TNF-α-induced IVD degeneration. Moreover, in vitro and in vivo experiments were performed to identify the potential role of CST in mitochondrial dysfunction, mitochondrial ROS generation and activation of the NLRP3 inflammasome during IVD degeneration. In addition, NF-κB signalling pathway activity was tested in NP tissues and cells from CST^-/- mice.

Results: The expression of CST in NP cells was diminished in the ageing- and TNF-α-induced IVD degeneration process. In addition, compared with WT mice, aged CST^-/- mice displayed accelerated metabolic imbalance and enhanced apoptosis, and these mice showed a disorganized NP tissue structure. Moreover, TNF-α-mediated catabolism and apoptosis were alleviated by exogenous CST treatment. Furthermore, CST inhibited mitochondrial dysfunction in NP cells through IVD degeneration and suppressed activation of the NLRP3 inflammasome. In vitro and ex vivo experiments indicated that increased NF-κB pathway activity might have been associated with the IVD degeneration observed in CST^-/- mice.

Conclusion: This study suggests the role of CST in mitochondrial ROS and activation of the NLRP3 inflammasome in IVD degeneration, which might shed light on therapeutic targets for IVD degeneration.

Keywords: Intervertebral disc degeneration, cortistatin, mitochondrial ROS, NF-κB signalling pathway, NLRP3

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APA

Zhao, Y., Qiu, C., Wang, W., Peng, J., Cheng, X., Shangguan, Y., Xu, M., Li, J., Qu, R., Chen, X., Jia, S., Luo, D., Liu, L., Li, P., Guo, F., Vasilev, K., Liu, L., Hayball, J., Dong, S., Pan, X., Li, Y., Guo, L., Cheng, L., Li, W. (2020). Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics, 10(15), 7015-7033. https://doi.org/10.7150/thno.45359.

ACS

Zhao, Y.; Qiu, C.; Wang, W.; Peng, J.; Cheng, X.; Shangguan, Y.; Xu, M.; Li, J.; Qu, R.; Chen, X.; Jia, S.; Luo, D.; Liu, L.; Li, P.; Guo, F.; Vasilev, K.; Liu, L.; Hayball, J.; Dong, S.; Pan, X.; Li, Y.; Guo, L.; Cheng, L.; Li, W. Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics 2020, 10 (15), 7015-7033. DOI: 10.7150/thno.45359.

NLM

CSE

Zhao Y, Qiu C, Wang W, Peng J, Cheng X, Shangguan Y, Xu M, Li J, Qu R, Chen X, Jia S, Luo D, Liu L, Li P, Guo F, Vasilev K, Liu L, Hayball J, Dong S, Pan X, Li Y, Guo L, Cheng L, Li W. 2020. Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation. Theranostics. 10(15):7015-7033.

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