TRPM2-mediated feed-forward loop promotes chondrocyte damage in osteoarthritis via calcium-cGAS-STING-NF-κB pathway

IF 11.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Journal of Advanced Research Pub Date : 2024-11-05 DOI:10.1016/j.jare.2024.11.007
Kai Sun, Xiong Zhang, Liangcai Hou, Fan Lu, Haigang Liu, Zehang Zheng, Zhou Guo, Jingting Xu, Zhaoxuan Ruan, Yanjun Hou, Junchen He, Fengjing Guo, Kaixiang Yang
{"title":"TRPM2-mediated feed-forward loop promotes chondrocyte damage in osteoarthritis via calcium-cGAS-STING-NF-κB pathway","authors":"Kai Sun, Xiong Zhang, Liangcai Hou, Fan Lu, Haigang Liu, Zehang Zheng, Zhou Guo, Jingting Xu, Zhaoxuan Ruan, Yanjun Hou, Junchen He, Fengjing Guo, Kaixiang Yang","doi":"10.1016/j.jare.2024.11.007","DOIUrl":null,"url":null,"abstract":"<h3>Introductions</h3>Osteoarthritis (OA) is a significant contributor to disability in the elderly population. However, current therapeutic options are limited. The transient receptor potential melastatin 2 (TRPM2) is involved in a range of disease processes, yet its role in OA remains unclear.<h3>Objectives</h3>To investigate the role of TRPM2 in OA.<h3>Methods</h3>Cartilage samples were collected from patients with osteoarthritis (OA) and mice with OA to examine TRPM2 expression levels. To investigate the effects of TRPM2 modulation on the destabilization of the medial meniscus (DMM) induced knee OA in mice, we utilized TRPM2 knockout mice and employed adenovirus-mediated overexpression of TRPM2. Furthermore, siRNA-mediated TRPM2 knockdown or plasmid-mediated TRPM2 overexpression was conducted to explore the role of TRPM2 in IL-1β-induced chondrocytes. The regulatory mechanism of IL-1β on TRPM2 expression was screened by signaling pathway inhibitors, and the transcription factors and binding sites of TRPM2 were predicted using the database. The binding of RELA (NF-κB-p65) to the Trpm2 promoter was verified by chip-PCR and ChIP-qPCR. The therapeutic potential of Ca<sup>2+</sup> chelation with BAPTA-AM for the treatment of osteoarthritis (OA) was investigated.<h3>Results</h3>An increased expression of TRPM2 was observed in the cartilage of OA patients and OA mice. Furthermore, mice deficient in Trpm2 exhibited a protective effect against DMM-induced OA progression. In contrast, TRPM2 overexpression resulted in exacerbation of DMM-induced OA and the<!-- --> <!-- -->promotion of an OA-like phenotype of chondrocytes. TRPM2 was upregulated by IL-1β in an NF-κB-p65-dependent manner. Subsequently, the TRPM2-Ca<sup>2+</sup>-mtDNA-cGAS-STING-NF-κB axis in the progression of OA was validated. Furthermore, inhibition of the TRPM2-Ca<sup>2+</sup> axis with BAPTA-AM effectively attenuated established OA.<h3>Conclusions</h3>Our data collectively revealed a pathological feedback loop involving TRPM2, Ca<sup>2+</sup>, mtDNA, cGAS, STING, and NF-κB in OA chondrocytes. This suggests that disrupting this loop could be a viable therapeutic approach for OA<strong>.</strong>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":null,"pages":null},"PeriodicalIF":11.4000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Advanced Research","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.jare.2024.11.007","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Introductions

Osteoarthritis (OA) is a significant contributor to disability in the elderly population. However, current therapeutic options are limited. The transient receptor potential melastatin 2 (TRPM2) is involved in a range of disease processes, yet its role in OA remains unclear.

Objectives

To investigate the role of TRPM2 in OA.

Methods

Cartilage samples were collected from patients with osteoarthritis (OA) and mice with OA to examine TRPM2 expression levels. To investigate the effects of TRPM2 modulation on the destabilization of the medial meniscus (DMM) induced knee OA in mice, we utilized TRPM2 knockout mice and employed adenovirus-mediated overexpression of TRPM2. Furthermore, siRNA-mediated TRPM2 knockdown or plasmid-mediated TRPM2 overexpression was conducted to explore the role of TRPM2 in IL-1β-induced chondrocytes. The regulatory mechanism of IL-1β on TRPM2 expression was screened by signaling pathway inhibitors, and the transcription factors and binding sites of TRPM2 were predicted using the database. The binding of RELA (NF-κB-p65) to the Trpm2 promoter was verified by chip-PCR and ChIP-qPCR. The therapeutic potential of Ca2+ chelation with BAPTA-AM for the treatment of osteoarthritis (OA) was investigated.

Results

An increased expression of TRPM2 was observed in the cartilage of OA patients and OA mice. Furthermore, mice deficient in Trpm2 exhibited a protective effect against DMM-induced OA progression. In contrast, TRPM2 overexpression resulted in exacerbation of DMM-induced OA and the promotion of an OA-like phenotype of chondrocytes. TRPM2 was upregulated by IL-1β in an NF-κB-p65-dependent manner. Subsequently, the TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB axis in the progression of OA was validated. Furthermore, inhibition of the TRPM2-Ca2+ axis with BAPTA-AM effectively attenuated established OA.

Conclusions

Our data collectively revealed a pathological feedback loop involving TRPM2, Ca2+, mtDNA, cGAS, STING, and NF-κB in OA chondrocytes. This suggests that disrupting this loop could be a viable therapeutic approach for OA.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
TRPM2介导的前馈环通过钙-cGAS-STING-NF-κB通路促进骨关节炎中软骨细胞的损伤
引言骨关节炎(OA)是导致老年人残疾的一个重要因素。然而,目前的治疗方案十分有限。方法收集骨关节炎(OA)患者和OA小鼠的软骨样本,检测TRPM2的表达水平。为了研究调节 TRPM2 对小鼠内侧半月板失稳(DMM)诱导的膝关节 OA 的影响,我们利用 TRPM2 基因敲除小鼠和腺病毒介导的 TRPM2 过表达。 此外,我们还进行了 siRNA 介导的 TRPM2 基因敲除或质粒介导的 TRPM2 过表达,以探讨 TRPM2 在 IL-1β 诱导的软骨细胞中的作用。通过信号通路抑制剂筛选了IL-1β对TRPM2表达的调控机制,并利用数据库预测了TRPM2的转录因子和结合位点。通过芯片-PCR和ChIP-qPCR验证了RELA(NF-κB-p65)与Trpm2启动子的结合。结果 在 OA 患者和 OA 小鼠的软骨中观察到 TRPM2 的表达增加。此外,缺乏 TRPM2 的小鼠对 DMM 诱导的 OA 进展具有保护作用。与此相反,TRPM2的过表达会导致DMM诱导的OA恶化,并促进软骨细胞OA样表型的形成。IL-1β以NF-κB-p65依赖的方式上调TRPM2。随后,TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB轴在OA进展中的作用得到了验证。此外,用 BAPTA-AM 抑制 TRPM2-Ca2+ 轴可有效减轻已形成的 OA。结论我们的数据共同揭示了 OA 软骨细胞中涉及 TRPM2、Ca2+、mtDNA、cGAS、STING 和 NF-κB 的病理反馈回路。这表明,破坏这一环路可能是治疗 OA 的一种可行方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Journal of Advanced Research
Journal of Advanced Research Multidisciplinary-Multidisciplinary
CiteScore
21.60
自引率
0.90%
发文量
280
审稿时长
12 weeks
期刊介绍: Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.
期刊最新文献
Lactate-mediated lactylation in human health and diseases: Progress and remaining challenges Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms Biological functions and pharmacological behaviors of bile acids in metabolic diseases Advanced machine learning schemes for prediction CO2 flux based experimental approach in underground coal fire areas Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1