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STMN1-IGFBP5轴诱导髓核细胞衰老和细胞外基质降解：体内和体外研究见解

STMN1-IGFBP5 axis induces senescence and extracellular matrix degradation in nucleus pulposus cells: In vivo and in vitro insights.

作者信息

Li Lei, Zhang Guangzhi, Yang Zhili, Cao Zhenyu, Wang Dongxin, Kang Xuewen

机构信息

Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China.

The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, 730000, P.R. China.

出版信息

Mol Med. 2025 May 3;31(1):167. doi: 10.1186/s10020-025-01220-7.

DOI:10.1186/s10020-025-01220-7
PMID:40319242
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12049776/
Abstract

Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1-IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.

摘要

衰老的髓核（NP）细胞诱导的细胞功能障碍是椎间盘退变（IDD）发病机制中的关键因素。Stathmin 1（STMN1）已被提出作为一种与端粒相关的衰老标志物，在许多与年龄相关的疾病的衰老过程中起作用。然而，其在NP细胞衰老中的作用仍不清楚。本研究表明，STMN1在人类退变的和自然衰老的大鼠NP组织标本中显著上调。体外模型表明，在复制性衰老和TNF-α诱导的NP衰老模型中，STMN1表达水平升高。慢病毒介导的STMN1敲低抑制了NP细胞衰老，而过表达则促进了NP细胞衰老，同时伴有细胞外基质（ECM）降解。深入的机制表明，胰岛素样生长因子结合蛋白5（IGFBP5）是STMN1的下游促衰老基因，在被STMN1上调后可诱导NP细胞衰老和ECM降解。此外，在尾椎间盘穿刺诱导的IDD大鼠模型中，STMN1敲低降低了IGFBP5表达并减轻了IDD的发展。结合上述结果，我们首次证明STMN1-IGFBP5轴可诱导NP细胞衰老和ECM降解，从而加速IDD的发展。这为开发针对IDD的分子靶向治疗提供了坚实的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/6d64bad04c14/10020_2025_1220_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/3a57f27b7bad/10020_2025_1220_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/bfdc859a9216/10020_2025_1220_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/530039560153/10020_2025_1220_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/d3cd66a84829/10020_2025_1220_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/c1ea1ce70d73/10020_2025_1220_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/b5c507f2a092/10020_2025_1220_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/d4f14f68589a/10020_2025_1220_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/64bf94e089c5/10020_2025_1220_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/6d64bad04c14/10020_2025_1220_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/3a57f27b7bad/10020_2025_1220_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/bfdc859a9216/10020_2025_1220_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/530039560153/10020_2025_1220_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/d3cd66a84829/10020_2025_1220_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/c1ea1ce70d73/10020_2025_1220_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/b5c507f2a092/10020_2025_1220_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/d4f14f68589a/10020_2025_1220_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/64bf94e089c5/10020_2025_1220_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28f5/12049776/6d64bad04c14/10020_2025_1220_Fig9_HTML.jpg

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[1]
STMN1-IGFBP5 axis induces senescence and extracellular matrix degradation in nucleus pulposus cells: In vivo and in vitro insights.

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本文引用的文献

[1]
Achilles' Heel-The Significance of Maintaining Microenvironmental Homeostasis in the Nucleus Pulposus for Intervertebral Discs.

Int J Mol Sci. 2023-11-22

[2]
Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Sci Transl Med. 2023-12-6

[3]
TMT-Based Proteomics Analysis of Senescent Nucleus Pulposus from Patients with Intervertebral Disc Degeneration.

Int J Mol Sci. 2023-8-26

[4]
Microtubule stabilization targeting regenerative chondrocyte cluster for cartilage regeneration.

Theranostics. 2023

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Aging, cell senescence, the pathogenesis and targeted therapies of intervertebral disc degeneration.

Front Pharmacol. 2023-5-5

[6]
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Biomolecules. 2023-4-18

[7]
Regulatory Effect of Inflammatory Mediators in Intervertebral Disc Degeneration.

Mediators Inflamm. 2023

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Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment.

Cell Prolif. 2023-9

[9]
Microtubule stabilization promotes the synthesis of type 2 collagen in nucleus pulposus cell by activating hippo-yap pathway.

Front Pharmacol. 2023-1-26

[10]
Discogenic Low Back Pain: Anatomy, Pathophysiology and Treatments of Intervertebral Disc Degeneration.

Int J Mol Sci. 2022-12-22

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