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Cited by 22Spine and Intervertebral Disc PathologyCellular Mechanics and InteractionsOsteoarthritis Treatment and Mechanisms

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Matrix stiffness regulates nucleus pulposus cell glycolysis by MRTF-A-dependent mechanotransduction

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Xu, Haoran, Wei, Kang, Ni, Jinhao, Deng, Xiaofeng, Wang, Yuexing, Xiang, Taiyang, Song, Fanglong, Wang, Qianliang, Niu, Yanping, Jiang, Fengxian, Wang, Jun, Sheng, Lei, Dai, Jun·2025·Bone Research
DOI 10.1038/s41413-025-00402-7PMC PMC11828926
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Abstract

Increased matrix stiffness of nucleus pulposus (NP) tissue is a main feature of intervertebral disc degeneration (IVDD) and affects various functions of nucleus pulposus cells (NPCs). Glycolysis is the main energy source for NPC survival, but the effects and underlying mechanisms of increased extracellular matrix (ECM) stiffness on NPC glycolysis remain unknown. In this study, hydrogels with different stiffness were established to mimic the mechanical environment of NPCs. Notably, increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis, and NPCs cultured on rigid substrates exhibited a reduction in glycolysis. Meanwhile, RNA sequencing analysis showed altered cytoskeleton-related gene expression in NPCs on rigid substrates. Myocardin-related transcription factor A (MRTF-A) is a transcriptional coactivator in mechanotransduction mainly responding to cytoskeleton remodeling, which was activated and translocated to the nucleus under rigid substrate and was upregulated during IVDD progression. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed that MRTF-A overexpression reduced NPC glycolytic metabolite abundance and identified a correlation with AMPK pathway. Mechanistically, rigid substrates and MRTF-A overexpression inhibited Kidins220 expression and AMPK phosphorylation in NPCs, whereas MRTF-A inhibition, treated with the MRTF-A inhibitor CCG, partially rescued NP tissue degeneration and glycolytic enzyme expression. Our data demonstrate that MRTF-A is a critical regulator that responds to increased matrix stiffness in IVDD, and MRTF-A activation reduces NPC glycolysis by down-regulating Kidins220 and inhibiting AMPK phosphorylation.

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Metadata

Authors
Xu, H., Wei, K., Ni, J., Deng, X., Wang, Y., Xiang, T., Song, F., Wang, Q., Niu, Y., Jiang, F., Wang, J., Sheng, L., & Dai, J.
Affiliations
  • Second Affiliated Hospital of Soochow University (CN)
  • Zhongnan Hospital of Wuhan University (CN)
  • Tongji Hospital (CN)
  • Sichuan University (CN)
Corresponding author
  • Wang, Jun
  • Sheng, Lei
  • Dai, Jun
ORCID
Venue
Bone Research
Publisher
Springer Science and Business Media LLC
Published
2025-02-14
Volume
13
Issue
1
Pages
23-23
ISSN
  • 2095-4700 (ISSN-L)
  • 2095-6231
DOI
10.1038/s41413-025-00402-7
PMC
PMC11828926
OpenAlex
W4407560352
Cited by
22
References
1
Citations by year
2026: 16 · 2025: 6
FWCI
14.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Bone Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81902179, 82002345)
  • Soochow University
  • Second Affiliated Hospital of Soochow University (SDFEYBS1905)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Spine and Intervertebral Disc Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
extracellular matrix stiffness, nucleus pulposus cells, glycolysis, MRTF-A, mechanotransduction, intervertebral disc degeneration, Kidins220, AMPK signaling, cytoskeletal remodeling, hydrogel stiffness
MeSH terms
Nucleus Pulposus, Adult, Animals, Cells, Cultured, Extracellular Matrix, Female, Glycolysis, Humans, Male, Middle Aged, Trans-Activators, Mechanotransduction, Cellular, Intervertebral Disc Degeneration

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