多组学分析显示VDR是间充质干细胞衰老的中心调节因子，与高脂饮食暴露后的骨质疏松症相关-动脉网

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure

Nature 等信源发布 2024-05-22 21:03

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AbstractThe consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis.

摘要高脂饮食（HFD）的摄入与骨质疏松症和脆性骨折的风险增加有关。然而，HFD诱导的骨质疏松症的具体机制尚不完全清楚。我们的研究表明，暴露于HFD会诱导骨髓间充质干细胞（BMSCs）过早衰老，降低其增殖和成骨能力，从而导致骨质疏松症。

Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters.

转录组学和染色质可及性分析显示，HFD喂养小鼠的BMSC中维生素D受体（VDR）结合序列的染色质可及性降低，VDR信号传导降低，表明VDR是BMSC衰老的关键调节因子。值得注意的是，向HFD喂养的小鼠施用VDR激活剂可挽救BMSC衰老并显着改善成骨，骨量和其他骨参数。

Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis..

从机制上讲，VDR激活通过降低细胞内活性氧（ROS）水平和保留线粒体功能来减少BMSC衰老。我们的研究结果不仅阐明了HFD诱导BMSC衰老和相关骨质疏松症的机制，而且通过靶向VDR-超氧化物歧化酶2（SOD2）-ROS轴为治疗HFD诱导的骨质疏松症提供了新的见解。。

IntroductionThe increasing prevalence of a high-fat diet (HFD, ≥30% of energy from fat) has raised concerns about its potential adverse impacts on health,1,2 including metabolic comorbidities such as obesity, diabetes, and nonalcoholic hepatitis,3,4,5,6,7 as well as its relationship with osteoporosis and bone fragility.8,9,10 HFD feeding results in the development of obesity, which is considered to protect against osteoporosis and osteoporotic fractures because of the positive effect of increased mechanical loading on the skeleton.11,12 However, accumulating research evidence shows that this effect is followed by decreased bone formation, bone turnover and an increased risk of fracture resulting from the development of metabolic impairment.8,13,14,15,16 For example, the dysregulation of lipid metabolism in the body attributed to HFD intake over an extended period can impair bone metabolism, resulting in bone loss and impaired fracture healing.8,9,10,17,18 However, how HFD-driven metabolic dysfunction impacts cellular function in bone tissue has not been determined.

引言高脂饮食（HFD，≥30%的脂肪能量）的日益流行引起了人们对其对健康的潜在不利影响的担忧，1,2包括肥胖，糖尿病和非酒精性肝炎等代谢性合并症，3,4,5,6,7及其与骨质疏松症和骨脆性的关系。8,9,10 HFD喂养导致肥胖的发展，由于骨骼机械负荷增加的积极作用，肥胖被认为可以预防骨质疏松症和骨质疏松性骨折。11,12然而，越来越多的研究证据表明，这种影响之后是骨形成减少，骨转换减少以及由于骨骼发育而导致的骨折风险增加代谢障碍。8,13,14,15,16例如，长期摄入HFD导致的体内脂质代谢失调会损害骨代谢，导致骨质流失和骨折愈合受损。8,9,10,17,18然而，HFD驱动的代谢功能障碍如何影响骨组织中的细胞功能尚未确定。

In general, a balance between osteoclast-dependent osteoclastogenesis and osteogenic cell-dependent osteogenesis is maintained to maintain bone mass and quality at a steady state.19,20 Nevertheless, HFD-induced osteoporosis differs from osteoporosis caused by other factors because it is characterized by reduced osteoclastogenic and osteogenic activity, suggesting that osteogenesis is a potential therapeutic target.18,21,22 The specific cellular mechanisms underlying these changes are yet to be fully understood.Studies have demonstrated the substantial role of bone marrow mesenchymal stem cell (BMSC) senescence in inadequate bone formation associated with osteoporosis,23,24 and a decrease in osteogenesis can l.

一般来说，破骨细胞依赖性破骨细胞生成和成骨细胞依赖性成骨之间的平衡得以维持，以维持骨量和质量处于稳定状态[19,20]。然而，HFD诱导的骨质疏松症不同于其他因素引起的骨质疏松症，因为它的特征是破骨细胞生成和成骨活性降低，这表明成骨是一个潜在的治疗靶点[18,21,22]。这些变化背后的具体细胞机制尚未完全了解。研究表明，骨髓间充质干细胞（BMSC）衰老在与骨质疏松症相关的骨形成不足中具有重要作用[23,24]，并且成骨减少可以减少。

Data availability

数据可用性

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (GSA: CRA012133 and CRA012134) of the National Genomics Data Center and are publicly accessible at https://ngdc.cncb.ac.cn/gsa.

本文报道的原始序列数据已保存在国家基因组学数据中心的基因组序列档案（GSA:CRA01133和CRA01134）中，可在https://ngdc.cncb.ac.cn/gsa.

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Download referencesAcknowledgementsThis work was supported by grants from the National Natural Science Foundation of China (grants No. 81873713 and No. U22A20157). Specifically, I would like to express my gratitude to Chichong Chan, who always stands by me. Many thanks to my colleagues, including Fang Liu, Jinyan Wu, Xinxing Lei and Junxiao Zhuo, for their support and to the investigators who performed the bioinformatics analyses and summarized the data available in this study.Author informationAuthor notesThese authors contributed equally: Jiayao Chen, Shuhong KuangAuthors and AffiliationsHospital of Stomatology, Sun Yat-sen University, Guangzhou, ChinaJiayao Chen, Shuhong Kuang, Jietao Cen, Yong Zhang, Zongshan Shen, Wei Qin, Qiting Huang, Xianling Gao, Fang Huang & Zhengmei LinGuangdong Provincial Key Laboratory of Stomatology, Guangzhou, ChinaJiayao Chen, Shuhong Kuang, Jietao Cen, Yong Zhang, Zongshan Shen, Wei Qin, Qiting Huang, Xianling Gao, Fang Huang & Zhengmei LinGuanghua School of Stomatology, Sun Yat-sen University, Guangzhou, ChinaJiayao Chen, Shuhong Kuang, Jietao Cen, Yong Zhang, Zongshan Shen, Wei Qin, Qiting Huang, Xianling Gao, Fang Huang & Zhengmei LinSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, ChinaZifeng WangAuthorsJiayao ChenView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了国家自然科学基金（批准号81873713和U22A20157）的资助。具体来说，我要感谢陈志忠，他一直支持我。非常感谢我的同事，包括刘芳，吴金燕，雷新兴和卓军，感谢他们的支持，感谢进行生物信息学分析并总结本研究可用数据的研究人员。作者信息作者注意到这些作者做出了同样的贡献：陈家耀，邝树红作者和附属机构广州中山大学口腔医学研究所陈家耀，邝树红，岑洁涛，张勇，沈宗山，秦伟，黄启庭，高仙灵，黄芳和黄正梅，广东省口腔医学重点实验室，陈家耀，邝树红，岑洁涛，张勇，沈宗山，秦伟，黄启庭，高仙灵，黄芳和黄正梅，中国广州中山大学口腔医学院陈，邝树红，岑洁涛，张勇，沈宗山，秦伟，黄启庭，高先玲，黄芳和郑梅，林森中山大学癌症中心，华南肿瘤学国家重点实验室，广州癌症医学协同创新中心，中国紫峰王作者陈家耀作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarShuhong KuangView author publicationsYou can also search for this author in

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PubMed Google ScholarYong ZhangView作者出版物您也可以在

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PubMed Google ScholarZongshan ShenView作者出版物您也可以在

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PubMed Google ScholarContributionsJiayao Chen performed the majority of the experiments, analyzed the data, and drafted the manuscript. Shuhong Kuang performed the in vivo experiments. Jietao Cen performed the in vitro experiments and drafted the manuscript. Zongshan Shen and Yong Zhang analyzed the data and edited the manuscript and figures.

PubMed谷歌学术贡献陈家耀进行了大部分实验，分析了数据，并起草了手稿。Kuang Shuhong进行了体内实验。岑洁涛进行了体外实验并起草了手稿。沈宗山和张勇分析了数据并编辑了手稿和数字。

Wei Qin, Qiting Huang, Zifeng Wang, and Xianling Gao made suggestions regarding the experiments and edited the manuscript. Zhengmei Lin and Fang Huang designed the study and edited the manuscript and figures. All the authors approved the final version of the manuscript.Corresponding authorsCorrespondence to.

秦伟，黄启亭，王子峰和高先灵就实验提出了建议并编辑了手稿。林正梅和黄方设计了这项研究，并编辑了手稿和数字。所有作者都批准了稿件的最终版本。通讯作者通讯。

Fang Huang or Zhengmei Lin.Ethics declarations

方煌或郑美林。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval

道德认可

All the experiments were conducted at Sun Yat-sen University with the approval of the Institutional Animal Care and Use Committee (SYSU-IACUC-2018-000269 and SYSU-IACUC-2021-000637).

所有实验均在中山大学进行，并得到机构动物护理和使用委员会（SYSU-IACUC-2018-000269和SYSU-IACUC-2021-000637）的批准。

Supplementary information41368_2024_309_MOESM1_ESM.pdfMultiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposureRights and permissions

补充信息41368\u 2024\u 309\u MOESM1\u ESM.pdfMultiomics分析显示VDR是间充质干细胞衰老的中枢调节剂，在高脂饮食暴露后与骨质疏松症有关权利和许可

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleChen, J., Kuang, S., Cen, J. et al. Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure.

转载和许可本文引用本文Chen，J.，Kuang，S.，Cen，J。等人。多组学分析显示VDR是间充质干细胞衰老的中枢调节因子，已知与高脂饮食暴露后的骨质疏松症有关。

Int J Oral Sci 16, 41 (2024). https://doi.org/10.1038/s41368-024-00309-9Download citationReceived: 20 October 2023Revised: 24 April 2024Accepted: 28 April 2024Published: 22 May 2024DOI: https://doi.org/10.1038/s41368-024-00309-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

国际口腔科学杂志16,41（2024）。https://doi.org/10.1038/s41368-024-00309-9Download引文接收日期：2023年10月20日修订日期：2024年4月24日接受日期：2024年4月28日发布日期：2024年5月22日OI：https://doi.org/10.1038/s41368-024-00309-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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