Upregulated CEMIP promotes intervertebral disc degeneration via AP-1-mediated change in chromatin accessibility

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-21 DOI:10.1002/ctm2.70322

Shibin Shu, Xin Zhang, Zhenhua Feng, Zhen Liu, Kaiyang Wang, Fengrui Li, Yating Wu, Bo Shi, Yong Qiu, Zezhang Zhu, Hongda Bao

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引用次数: 0

Abstract

Background

Intervertebral disc degeneration (IDD), a chronic and multifactorial skeletal disorder, is the primary cause of low back pain. It results in reduced disc height and nucleus pulposus hydration due to proteoglycan loss and nucleus pulposus cells (NPCs) dysfunction within a hypoxic microenvironment. Metabolic dysregulation initiates catabolic processes, leading to extracellular matrix (ECM) degradation and compromising disc biomechanical integrity. Emerging evidence highlights epigenetic modifications as pivotal in IDD, influencing NPC gene expression transcriptionally and post-transcriptionally.

Methods

In order to understand the epigenetic underpinnings of IDD, our study provided a comprehensive profile of chromatin accessibility changes in degenerated NPCs using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq).

Results

With motif enrichment analysis, we identified the activator protein-1 (AP-1) transcription factor critical in driving the chromatin accessibility changes during IDD. Integrative ATAC-seq and transcriptional profiling revealed cell migration-inducing protein (CEMIP) as a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD. Furthermore, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP. Elevated CEMIP plasma levels correlated with clinical IDD severity, and CEMIP knockout mice demonstrated improved IDD.

Conclusions

Mechanistically, CEMIP disrupted ECM homeostasis through its regulation of high molecular weight hyaluronic acid (HMW-HA) degradation, and its contribution to fibrotic changes. Our findings highlight CEMIP's vital role in IDD and identify the AP-1 family as a critical regulator of IDD, providing new potential therapeutic targets for novel IDD interventions.

Key points

Integrative ATAC-seq and transcriptional profiling revealed CEMIPas a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD.
Further, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP.
Elevated CEMIP plasma levels correlated with clinical IDD severity, and CEMIP knockout mice demonstrated improved IDD.
Mechanistically, CEMIP disrupted extracellular matrix homeostasis through its regulation of high molecular weight hyaluronic acid degradation, and its contribution to fibrotic changes.
Our findings offer new avenues for IDD treatment strategies, with the potential to alleviate the global burden of back pain.

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上调的CEMIP通过ap -1介导的染色质可及性改变促进椎间盘退变

背景椎间盘退变（IDD）是一种慢性多因素骨骼疾病，是腰痛的主要原因。在缺氧微环境下，由于蛋白聚糖的损失和髓核细胞的功能障碍，导致椎间盘高度降低和髓核水化。代谢失调启动分解代谢过程，导致细胞外基质（ECM）降解，损害椎间盘生物力学完整性。新出现的证据强调表观遗传修饰在IDD中起关键作用，通过转录和转录后影响NPC基因表达。方法为了了解IDD的表观遗传学基础，我们的研究使用转座酶可及染色质高通量测序法（ATAC-seq）提供了退化npc染色质可及性变化的综合描述。结果通过基序富集分析，我们确定了在IDD期间驱动染色质可及性变化的关键激活蛋白-1 （AP-1）转录因子。综合ATAC-seq和转录分析显示，细胞迁移诱导蛋白（CEMIP）是IDD的关键生物标志物和贡献者，在IDD中表现出显著的上调。此外，我们证明AP-1家族，特别是c-Fos，协调了CEMIP的上调。血浆中CEMIP水平升高与临床IDD严重程度相关，且CEMIP敲除小鼠表现出IDD改善。从机制上看，CEMIP通过调节高分子量透明质酸（HMW-HA）的降解破坏了ECM的内稳态，并参与了纤维化的改变。我们的研究结果强调了CEMIP在IDD中的重要作用，并确定AP-1家族是IDD的关键调节因子，为新型IDD干预提供了新的潜在治疗靶点。综合ATAC-seq和转录分析显示，CEMIPas是IDD的关键生物标志物和贡献者，在IDD中表现出显著的上调。此外，我们证明AP-1家族，特别是c-Fos，协调了CEMIP的上调。血浆中CEMIP水平升高与临床IDD严重程度相关，且CEMIP敲除小鼠表现出IDD改善。在机制上，CEMIP通过调节高分子量透明质酸的降解，破坏细胞外基质的稳态，并促进纤维化的改变。我们的发现为IDD治疗策略提供了新的途径，有可能减轻全球背部疼痛的负担。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.