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Compensatory upregulation of MT2A alleviates neurogenic intermittent claudication through inhibiting activated p38 MAPK-mediated neuronal apoptosis

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Abstract

Neurogenic intermittent claudication (NIC), a classic symptom of lumbar spinal stenosis (LSS), is associated with neuronal apoptosis. To explore the novel therapeutic target of NIC treatment, we constructed the rat model of NIC by cauda equina compression (CEC) method and collected dorsal root ganglion (DRG) tissues, a region responsible for sensory and motor function, for mRNA sequencing. Bioinformatic analysis of mRNA sequencing indicated that upregulated metallothionein 2A (MT2A), an apoptosis-regulating gene belonging to the metallothionein family, might participate in NIC progression. Activated p38 MAPK mediated motor dysfunction following LSS and it was also found in DRG tissues of rats with NIC. Therefore, we supposed that MT2A might affect NIC progression by regulating p38 MAPK pathway. Then the rat model of NIC was used to explore the exact role of MT2A. Rats at day 7 post-CEC exhibited poorer motor function and had two-fold MT2A expression in DRG tissues compared with rats with sham operation. Co-localization analysis showed that MT2A was highly expressed in neurons, but not in microglia or astrocytes. Subsequently, neurons isolated from DRG tissues of rats were exposed to hypoxia condition (3% O2, 92% N2, 5% CO2) to induce cell damage. Gain of MT2A function in neurons was performed by lentivirus-mediated overexpression. MT2A overexpression inhibited apoptosis by inactivating p38 MAPK in hypoxia-exposed neurons. Our findings indicated that high MT2A expression was related to NIC progression, and MT2A overexpression protected against NIC through inhibiting activated p38 MAPK-mediated neuronal apoptosis in DRG tissues.

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Data availability

The data that support the findings of the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (82071365).

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  1. Chenggang Wang and Zhanchao Wang contributed equally to this research.

Authors and Affiliations

  1. Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Chenggang Wang, Xuejian Dan, Jiahui Xu, Jingwei Zhao, Wei Xu, Zhourui Wu, Wei Liu & Bin Ma

  2. Department of Orthopedics, Chongming Hospital Affiliated to Shanghai University of Medicine and Health Sciences, Shanghai, China

    Zhanchao Wang

  3. Department of Orthopedics, Air Force Hospital of the Northern Theater of Chinese People’s Liberation Army (PLA), Shenyang, Liaoning, China

    Ying Zi

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  1. Chenggang Wang
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Contributions

C.G. W. and Z.C. W.: conceptualization, interpretation of results, and writing—original draft. Y. Z., X.J. D., and J.H. X.: investigation and data collection. J.W. Z, W. X., Z.R. W., and W. L.: data analysis and visualization. B. M.: conceptualization and writing—review and editing.

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Correspondence to Bin Ma.

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Animal experiments were approved by the Animal Welfare Ethics Committee of Tongji Hospital (Approval number: 2021-DW-(101)). All operations were performed in accordance with the US National Research Council's Guide for the Care and Use of Laboratory Animals.

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Wang, C., Wang, Z., Zi, Y. et al. Compensatory upregulation of MT2A alleviates neurogenic intermittent claudication through inhibiting activated p38 MAPK-mediated neuronal apoptosis. Human Cell 37, 675–688 (2024). https://doi.org/10.1007/s13577-024-01043-4

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