AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026020011
Submit to EJMO
Cite this article
3
Download
10
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Piezo1 activation promotes intervertebral disc degeneration via the calpain-2/BAX/caspase-3 apoptosis signaling axis

Bifeng Fu1 ,  Pengtao Huang1 ,  Mingwei Wang1 ,  Xilin Gao1 ,  Weimin Wang1 ,  Aifeng Liu1 ,  Chao Zhang1 ,  Xiaoqing Zhang1 ,  Qiujin Hao1* ,  Yuping Gao2*
Show Less
1 Department of Traditional Chinese Orthopedics and Traumatology Ward, National Clinical Research Center for Chinese Medicine, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
2 Department of Scientific Research, Clinical College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
EJMO, 026020011 https://doi.org/10.36922/EJMO026020011
Received: 7 January 2026 | Revised: 16 January 2026 | Accepted: 21 January 2026 | Published online: 13 March 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
XML
Cite
Abstract

Introduction: Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain; however, the mechanisms of mechanotransduction linking abnormal mechanical stress to disc cell apoptosis remain incompletely understood.

Objective: This study aims to investigate how the mechanosensitive ion channel Piezo1 regulates the calpain-2–mediated non-classical apoptotic pathway in IDD.

Methods: Human nucleus pulposus (NP) tissues with different Pfirrmann grades (II–V) were collected. The expression levels of Piezo1, calpain-2, Bcl-2–associated X protein (BAX), and cleaved caspase-3 were analyzed using Western blotting, immunohistochemistry, and transcriptome sequencing. An ex vivo rabbit spinal mechanical degeneration model was established to validate the impact of mechanical load on this signaling axis.

Results: In degenerated human NP tissues, the expression of Piezo1, calpain-2, BAX, and cleaved caspase-3 was upregulated with increasing degeneration grade. Transcriptome analysis revealed significant enrichment of apoptosis and inflammation pathways in the high-degeneration group. Ex vivo mechanical experiments confirmed that sustained compressive stress upregulated Piezo1 expression and exacerbated tissue degeneration and cell apoptosis.

Conclusion: The findings demonstrate that a novel Piezo1/calpain-2/BAX/caspase-3 signaling axis converts aberrant mechanical signals into apoptotic events, thereby driving the progression of IDD.

Keywords
Piezo1
Calpain-2/Bcl-2–associated X protein /caspase-3 signaling axis
Apoptosis
Intervertebral disc degeneration
Mechanotransduction
Funding
This work was supported by the Tianjin Municipal Education Commission projects (2023KJ156 and 2024KJ041); the Tianjin University of Traditional Chinese Medicine Institute of Orthopedics and Traumatology (2024GSQ02); the Tianjin University of Traditional Chinese Medicine First Affiliated Hospital “Innovation and Development Project” (ZZ2024010); and the Tianjin University of Traditional Chinese Medicine First Affiliated Hospital Innovation Team Cultivation Program (4042502041).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
  1. Wang Y, Cheng H, Wang T, et al. Oxidative stress in intervertebral disc degeneration: molecular mechanisms, pathogenesis and treatment. Cell Prolif. 2023;56(9):e13448. doi: 10.1111/cpr.13448

 

  1. Kang L, Zhang H, Jia C, et al. Targeting oxidative stress and inflammation in intervertebral disc degeneration: therapeutic perspectives of phytochemicals. Front Pharmacol. 2022;13:956355. doi: 10.3389/fphar.2022.956355

 

  1. Baumann A, Hernandez-Arriaga A, Brandt A, et al. Microbiota profiling in aging-associated inflammation and liver degeneration. Int J Med Microbiol. 2021;311(4):151500. doi: 10.1016/j.ijmm.2021.151500

 

  1. Sarkar D, Fisher PB. Molecular mechanisms of agingassociated inflammation. Cancer Lett. 2006;236(1):13-23. doi: 10.1016/j.canlet.2005.04.009

 

  1. Chiarotto A, Koes BW. Nonspecific low back pain. N Engl J Med. 2022;386(18):1732-1740. doi: 10.1056/NEJMcp2032396

 

  1. Xiao M, Ni S. Different effects of abnormal mechanical stress on temporomandibular joint cartilage, subchondral bone, and discs. Front Physiol. 2025;16:1539342. doi: 10.3389/fphys.2025.1539342

 

  1. Du J, Sun X, Ao L, et al. Impact of abnormal mechanical stress on chondrocyte death in osteoarthritis. Med Sci Monit. 2025;31:e948290. doi: 10.12659/MSM.948290

 

  1. Seidler A, Schubert M, Freiberg A, et al. Psychosocial occupational exposures and mental illness. Dtsch Arztebl Int. 2022;119(42):709-715. doi: 10.3238/arztebl.m2022.0295

 

  1. Inoue N, Otsui K, Yoshioka T, et al. A simultaneous evaluation of occupational stress and depression in patients with lifestyle-related diseases. Intern Med. 2016;55(9):1071-1075. doi: 10.2169/internalmedicine.55.5920

 

  1. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44-56. doi: 10.1038/nrrheum.2013.160

 

  1. Chen F, Lei L, Chen S, et al. Serglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration. Nat Commun. 2024;15(1):47. doi: 10.1038/s41467-023-44313-9

 

  1. Wang Y, Li Z, Wang P, et al. Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: mechanisms, bone metabolism disruption, and therapeutic strategies. World J Diabetes. 2025;16(6):106720. doi: 10.4239/wjd.v16.i6.106720

 

  1. Shao T, Gao Q, Ma Y, et al. Hyperforin improves matrix stiffness-induced nucleus pulposus inflammatory degeneration by activating mitochondrial fission. Int Immunopharmacol. 2024;137:112444. doi: 10.1016/j.intimp.2024.112444

 

  1. Zhang X, Shu S, Feng Z, et al. Microtubule stabilization promotes the synthesis of type II collagen in nucleus pulposus cells by activating the Hippo-YAP pathway. Front Pharmacol. 2023;14:1102318. doi: 10.3389/fphar.2023.1102318

 

  1. Wang S, Li J, Tian J, et al. High amplitude and low frequency cyclic mechanical strain promotes degeneration of human nucleus pulposus cells via the NF-κB p65 pathway. J Cell Physiol. 2018;233(9):7206-7216. doi: 10.1002/jcp.26551

 

  1. Coste B, Xiao B, Santos JS, et al. Piezo proteins are poreforming subunits of mechanically activated channels. Nature. 2012;483(7388):176-181. doi: 10.1038/nature10812

 

  1. Coste B, Mathur J, Schmidt M, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010;330(6000):55-60. doi: 10.1126/science.1193270

 

  1. Chen S, Li Z, Zhang J, et al. Piezo1 at the crossroads: mediating inflammation and mechanical stress in joint disorders. Joint Bone Spine. 2025;93(2):105953. doi: 10.1016/j.jbspin.2025.105953

 

  1. Xie R, Hu X, Zheng L, et al. Calpain-2 activity promotes aberrant endoplasmic reticulum stress-related apoptosis in hepatocytes. World J Gastroenterol. 2020;26(13):1450-1462. doi: 10.3748/wjg.v26.i13.1450

 

  1. Liu C, Gao X, Lou J, et al. Aberrant mechanical loading induces annulus fibrosus cell apoptosis in intervertebraldisc degeneration via mechanosensitive ion channel Piezo1. Arthritis Res Ther. 2023;25(1):117. doi: 10.1186/s13075-023-03093-9

 

  1. Yin XL, Jin ZF, Zhu LG, et al. Effect and mechanism of mechanical factors on intervertebral disc degeneration. Chin J Tissue Eng Res. 2022;26(12):1816-1821. [In Chinese] doi: 10.12307/2022.501

 

  1. Han T, Luo P, Cai C, et al. The influence of different stress loading on the biomechanics of motion segments in isolated rabbit spines. J Biomech. 2025;182:112592. doi: 10.1016/j.jbiomech.2025.112592

 

  1. Jin C, Su S, Yu S, et al. Essential roles of PIEZO1 in the mammalian cardiovascular system: from development to diseases. Cells. 2024;13(17):1422. doi: 10.3390/cells13171422

 

  1. Bai C, Tang M. Effects of CdTe quantum dot exposure on the calcium signaling pathway in rat dorsal root ganglion cells ND7/23. Toxicology. 2025;517:154212. doi: 10.1016/j.tox.2025.154212

 

  1. Panaretakis T, Pokrovskaja K, Shoshan MC, et al. Interferonalpha-induced apoptosis in U266 cells is associated with activation of the proapoptotic Bcl-2 family members Bak and Bax. Oncogene. 2003;22(29):4543-4556. doi: 10.1038/sj.onc.1206503

 

  1. Liu Z, Ma G, Li J, et al. Directing the electrochemical C–N coupling toward efficient amide synthesis via ammonia activation-mediated pathway. Angew Chem Int Ed Engl. 2025;64(52):e202518108. doi: 10.1002/anie.202518108

 

  1. Schierle CF, Berkmen M, Huber D, et al. The DsbA signal sequence directs efficient cotranslational export of passenger proteins to the Escherichia coli periplasm via the signal recognition particle pathway. J Bacteriol. 2003;185(19):5706-5713. doi: 10.1128/JB.185.19.5706-5713.2003

 

  1. Dunlop KM, Jones DOB, Sweetman AK. Direct evidence of an efficient energy transfer pathway from jellyfish carcasses to a commercially important deep-water species. Sci Rep. 2017;7(1):17455. doi: 10.1038/s41598-017-17557-x

 

  1. He R, Cui M, Lin H, et al. Melatonin resists oxidative stress-induced apoptosis in nucleus pulposus cells. Life Sci. 2018;199:122-130. doi: 10.1016/j.lfs.2018.03.020

 

  1. Zhan J, Wang S, Feng M, et al. Effects of axial compression and distraction on vascular bud and VEGFA expression in the vertebral endplate of an ex vivo rabbit spinal motion segment culture model. Spine. 2021;46(7):421-432. doi: 10.1097/BRS.0000000000003816
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept