{"title":"终板软骨细胞衍生的外泌体miR-128-3p通过miR-128-3p/TRAF6轴靶向TRAF6以抑制热蛋白沉积,从而缓解椎间盘退变。","authors":"Qiuwei Li, Ruocheng Guo, Zuomeng Wu, Chenhao Zhao, Xuewu Chen, Hong Wang, Cailiang Shen","doi":"10.1016/j.intimp.2024.113620","DOIUrl":null,"url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain and significantly impacts quality of life. The pathogenesis of IVDD is largely driven by inflammation, pyroptosis, and extracellular matrix (ECM) degradation, which current therapies fail to adequately address. In this study, we explore the therapeutic potential of exosomes derived from endplate chondrocytes (EPCs), with a particular focus on the microRNA miR-128-3p. Our findings reveal that exosomes isolated from third-generation EPCs, enriched with miR-128-3p, exhibit potent anti-inflammatory and anti-pyroptotic effects in lipopolysaccharide-treated nucleus pulposus cells, which are key contributors to IVDD pathology. Specifically, we demonstrate that miR-128-3p delivered via EPC-derived exosomes directly targets TRAF6, effectively suppressing activation of the NF-κB signaling pathway, which is known to play a pivotal role in inflammation and ECM breakdown, leading to a marked reduction in pro-inflammatory cytokine release and mitigation of ECM degradation. Importantly, third-generation EPC exosomes, with higher levels of miR-128-3p, showed superior efficacy compared to fifth-generation EPCs, underscoring the critical role of miR-128-3p in mediating these protective effects. Our research highlights the promise of EPC-derived exosomes, particularly those rich in miR-128-3p, as a novel, cell-free therapeutic approach for IVDD. Unlike current treatments that focus primarily on symptom management, our approach targets key molecular pathways underlying IVDD progression, including inflammation, pyroptosis, and ECM degradation. By elucidating the miR-128-3p/TRAF6 axis, this study provides a foundation for the development of targeted, biologically based interventions aimed at halting or even reversing IVDD, thereby offering hope for more effective and lasting therapeutic options.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"143 Pt 3","pages":"113620"},"PeriodicalIF":4.8000,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Endplate chondrocyte-derived exosomal miR-128-3p mitigates intervertebral disc degeneration by targeting TRAF6 via the miR-128-3p/TRAF6 axis to suppress pyroptosis.\",\"authors\":\"Qiuwei Li, Ruocheng Guo, Zuomeng Wu, Chenhao Zhao, Xuewu Chen, Hong Wang, Cailiang Shen\",\"doi\":\"10.1016/j.intimp.2024.113620\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain and significantly impacts quality of life. The pathogenesis of IVDD is largely driven by inflammation, pyroptosis, and extracellular matrix (ECM) degradation, which current therapies fail to adequately address. In this study, we explore the therapeutic potential of exosomes derived from endplate chondrocytes (EPCs), with a particular focus on the microRNA miR-128-3p. Our findings reveal that exosomes isolated from third-generation EPCs, enriched with miR-128-3p, exhibit potent anti-inflammatory and anti-pyroptotic effects in lipopolysaccharide-treated nucleus pulposus cells, which are key contributors to IVDD pathology. Specifically, we demonstrate that miR-128-3p delivered via EPC-derived exosomes directly targets TRAF6, effectively suppressing activation of the NF-κB signaling pathway, which is known to play a pivotal role in inflammation and ECM breakdown, leading to a marked reduction in pro-inflammatory cytokine release and mitigation of ECM degradation. Importantly, third-generation EPC exosomes, with higher levels of miR-128-3p, showed superior efficacy compared to fifth-generation EPCs, underscoring the critical role of miR-128-3p in mediating these protective effects. Our research highlights the promise of EPC-derived exosomes, particularly those rich in miR-128-3p, as a novel, cell-free therapeutic approach for IVDD. Unlike current treatments that focus primarily on symptom management, our approach targets key molecular pathways underlying IVDD progression, including inflammation, pyroptosis, and ECM degradation. By elucidating the miR-128-3p/TRAF6 axis, this study provides a foundation for the development of targeted, biologically based interventions aimed at halting or even reversing IVDD, thereby offering hope for more effective and lasting therapeutic options.</p>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":\"143 Pt 3\",\"pages\":\"113620\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-12-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International immunopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.intimp.2024.113620\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/16 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.intimp.2024.113620","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/16 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Endplate chondrocyte-derived exosomal miR-128-3p mitigates intervertebral disc degeneration by targeting TRAF6 via the miR-128-3p/TRAF6 axis to suppress pyroptosis.
Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain and significantly impacts quality of life. The pathogenesis of IVDD is largely driven by inflammation, pyroptosis, and extracellular matrix (ECM) degradation, which current therapies fail to adequately address. In this study, we explore the therapeutic potential of exosomes derived from endplate chondrocytes (EPCs), with a particular focus on the microRNA miR-128-3p. Our findings reveal that exosomes isolated from third-generation EPCs, enriched with miR-128-3p, exhibit potent anti-inflammatory and anti-pyroptotic effects in lipopolysaccharide-treated nucleus pulposus cells, which are key contributors to IVDD pathology. Specifically, we demonstrate that miR-128-3p delivered via EPC-derived exosomes directly targets TRAF6, effectively suppressing activation of the NF-κB signaling pathway, which is known to play a pivotal role in inflammation and ECM breakdown, leading to a marked reduction in pro-inflammatory cytokine release and mitigation of ECM degradation. Importantly, third-generation EPC exosomes, with higher levels of miR-128-3p, showed superior efficacy compared to fifth-generation EPCs, underscoring the critical role of miR-128-3p in mediating these protective effects. Our research highlights the promise of EPC-derived exosomes, particularly those rich in miR-128-3p, as a novel, cell-free therapeutic approach for IVDD. Unlike current treatments that focus primarily on symptom management, our approach targets key molecular pathways underlying IVDD progression, including inflammation, pyroptosis, and ECM degradation. By elucidating the miR-128-3p/TRAF6 axis, this study provides a foundation for the development of targeted, biologically based interventions aimed at halting or even reversing IVDD, thereby offering hope for more effective and lasting therapeutic options.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.