Hua Jin , Mengmeng Chen , Xiyu Wang , Guangyong Sun , Hao Chen , Dong Zhang
{"title":"雌激素缺乏影响绝经后骨质疏松双阴性T细胞功能,激活NF-κB","authors":"Hua Jin , Mengmeng Chen , Xiyu Wang , Guangyong Sun , Hao Chen , Dong Zhang","doi":"10.1016/j.bbrc.2025.152212","DOIUrl":null,"url":null,"abstract":"<div><div>Postmenopausal osteoporosis (PMOP), which is driven primarily by estrogen deficiency, is characterized by excessive bone resorption and disrupted immune homeostasis. Although immune system contributions to bone loss are well-documented, the roles of specific regulatory subsets, such as double-negative T (DNT) cells (CD3<sup>+</sup>TCRαβ<sup>+</sup>CD4<sup>−</sup>CD8<sup>−</sup>NK1.1<sup>−</sup>), remain unclear. Herein, by using an ovariectomized (OVX) mouse model of PMOP, we integrated transcriptomic profiling, <em>in vivo</em> functional assays, and <em>in vitro</em> studies to investigate DNT cell alterations. The OVX mice presented significant reductions in both DNT cell frequency and immunoregulatory capacity, which were accompanied by their increased apoptosis and suppressed proliferation. RNA sequencing revealed concurrent upregulation of NF-κB signaling and apoptotic pathways with downregulation of estrogen receptor (ER) signaling and cytotoxicity. <em>In vitro</em>, estrogen stimulation enhanced DNT cell immunoregulatory function and estrogen receptor <em>Esr1</em> expression, while inhibiting NF-κB activation. These results demonstrated that estrogen deficiency impaired DNT cell viability and function, potentially through NF-κB pathway activation, thereby exacerbating immune dysregulation in PMOP. Our study suggests that DNT cells may represent important immune players involved in osteoimmunology and potential targets for immunomodulatory therapies of osteoporosis.</div></div>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"776 ","pages":"Article 152212"},"PeriodicalIF":2.2000,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Estrogen deficiency impairs double-negative T cell function and activates NF-κB in postmenopausal osteoporosis\",\"authors\":\"Hua Jin , Mengmeng Chen , Xiyu Wang , Guangyong Sun , Hao Chen , Dong Zhang\",\"doi\":\"10.1016/j.bbrc.2025.152212\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Postmenopausal osteoporosis (PMOP), which is driven primarily by estrogen deficiency, is characterized by excessive bone resorption and disrupted immune homeostasis. Although immune system contributions to bone loss are well-documented, the roles of specific regulatory subsets, such as double-negative T (DNT) cells (CD3<sup>+</sup>TCRαβ<sup>+</sup>CD4<sup>−</sup>CD8<sup>−</sup>NK1.1<sup>−</sup>), remain unclear. Herein, by using an ovariectomized (OVX) mouse model of PMOP, we integrated transcriptomic profiling, <em>in vivo</em> functional assays, and <em>in vitro</em> studies to investigate DNT cell alterations. The OVX mice presented significant reductions in both DNT cell frequency and immunoregulatory capacity, which were accompanied by their increased apoptosis and suppressed proliferation. RNA sequencing revealed concurrent upregulation of NF-κB signaling and apoptotic pathways with downregulation of estrogen receptor (ER) signaling and cytotoxicity. <em>In vitro</em>, estrogen stimulation enhanced DNT cell immunoregulatory function and estrogen receptor <em>Esr1</em> expression, while inhibiting NF-κB activation. These results demonstrated that estrogen deficiency impaired DNT cell viability and function, potentially through NF-κB pathway activation, thereby exacerbating immune dysregulation in PMOP. Our study suggests that DNT cells may represent important immune players involved in osteoimmunology and potential targets for immunomodulatory therapies of osteoporosis.</div></div>\",\"PeriodicalId\":8779,\"journal\":{\"name\":\"Biochemical and biophysical research communications\",\"volume\":\"776 \",\"pages\":\"Article 152212\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2025-06-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical and biophysical research communications\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0006291X25009271\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical and biophysical research communications","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006291X25009271","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Estrogen deficiency impairs double-negative T cell function and activates NF-κB in postmenopausal osteoporosis
Postmenopausal osteoporosis (PMOP), which is driven primarily by estrogen deficiency, is characterized by excessive bone resorption and disrupted immune homeostasis. Although immune system contributions to bone loss are well-documented, the roles of specific regulatory subsets, such as double-negative T (DNT) cells (CD3+TCRαβ+CD4−CD8−NK1.1−), remain unclear. Herein, by using an ovariectomized (OVX) mouse model of PMOP, we integrated transcriptomic profiling, in vivo functional assays, and in vitro studies to investigate DNT cell alterations. The OVX mice presented significant reductions in both DNT cell frequency and immunoregulatory capacity, which were accompanied by their increased apoptosis and suppressed proliferation. RNA sequencing revealed concurrent upregulation of NF-κB signaling and apoptotic pathways with downregulation of estrogen receptor (ER) signaling and cytotoxicity. In vitro, estrogen stimulation enhanced DNT cell immunoregulatory function and estrogen receptor Esr1 expression, while inhibiting NF-κB activation. These results demonstrated that estrogen deficiency impaired DNT cell viability and function, potentially through NF-κB pathway activation, thereby exacerbating immune dysregulation in PMOP. Our study suggests that DNT cells may represent important immune players involved in osteoimmunology and potential targets for immunomodulatory therapies of osteoporosis.
期刊介绍:
Biochemical and Biophysical Research Communications is the premier international journal devoted to the very rapid dissemination of timely and significant experimental results in diverse fields of biological research. The development of the "Breakthroughs and Views" section brings the minireview format to the journal, and issues often contain collections of special interest manuscripts. BBRC is published weekly (52 issues/year).Research Areas now include: Biochemistry; biophysics; cell biology; developmental biology; immunology
; molecular biology; neurobiology; plant biology and proteomics