{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T22:43:19Z","timestamp":1782772999443,"version":"3.54.5"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We exploited a rat needle model to investigate digoxin\u2019s role in intervertebral disc degeneration <jats:italic>in vivo<\/jats:italic>. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&amp;amp;E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-\u03b1-induced inflammatory effects <jats:italic>in vitro<\/jats:italic>. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-\u03b1-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1251517","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T07:33:06Z","timestamp":1695108786000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Digoxin protects against intervertebral disc degeneration via TNF\/NF-\u03baB and LRP4 signaling"],"prefix":"10.3389","volume":"14","author":[{"given":"Qunbo","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenchuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlu","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9158","DOI":"10.3390\/ijerph19159158","article-title":"Non-specific low back pain, dietary salt intake, and posterior lumbar subcutaneous edema","volume":"19","author":"Brown","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"B2","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0140-6736(21)00733-9","article-title":"Low back pain","volume":"398","author":"Knezevic","year":"2021","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00098-X","article-title":"Global, regional, and national burden of low back pain, 1990\u20132020, its attributable risk factors, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021","volume":"5","author":"Ferreira","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00783-7","article-title":"Mechanisms and clinical implications of intervertebral disc calcificat ion","volume":"18","author":"Zehra","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v041a24","article-title":"Intervertebral disc degeneration and regeneration: a motion segment pe rspective","volume":"41","author":"Ashinsky","year":"2021","journal-title":"Eur Cells Materials"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.687024","article-title":"Fexofenadine protects against intervertebral disc degeneration through TNF signaling","volume":"9","author":"Liu","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2240894","DOI":"10.1155\/2022\/1835900","article-title":"Hydroxytyrosol ameliorates intervertebral disc degeneration and neurop athic pain by reducing oxidative stress and inflammation","author":"Yu","year":"2022","journal-title":"Oxid Med Cell Longevity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41584-021-00713-z","article-title":"A new immunometabolic perspective of intervertebral disc degeneration","volume":"18","author":"Francisco","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-023-07717-1","article-title":"The importance of inflammatory biomarkers in non-specific acute and chronic low back pain: a systematic review","author":"Pinto","year":"2023","journal-title":"Eur Spine J"},{"key":"B11","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1186\/s13018-021-02545-9","article-title":"Vitamin D inhibits TNF-\u03b1 induced apoptosis of human nucleus pulposus cells through regulation of NF-kB signaling pathway","volume":"16","author":"Zhang","year":"2021","journal-title":"J Orthopaedic Surg Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1835900","DOI":"10.1155\/2022\/1835900","article-title":"USP7 Attenuates Endoplasmic Reticulum Stress and NF-\u03baB Signalin g to Modulate Chondrocyte Proliferation, Apoptosis, and Inflammatory R esponse under Inflammation","author":"Dong","year":"2022","journal-title":"Oxid Med Cell Longevity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00753-9","article-title":"Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-\u03b2-mediated Smad2\/3 phosphorylation","volume":"54","author":"Chen","year":"2022","journal-title":"Exp Mol Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.5455\/medarh.2022.76.23-28","article-title":"Digoxin impact on heart failure patients with atrial fibrillation","volume":"76","author":"Gerakaris","year":"2022","journal-title":"Med Arch"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.01.051","article-title":"The use of digoxin in patients with worsening chronic heart failure: r econsidering an old drug to reduce hospital admissions","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1139\/y04-041","article-title":"Endoxin-mediated myocardial ischemia reperfusion injury in rats in vit ro","volume":"82","author":"Ke","year":"2004","journal-title":"Can J Physiol Pharmacol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2016.03.011","article-title":"Digoxin: The good and the bad","volume":"26","author":"Ziff","year":"2016","journal-title":"Trends Cardiovasc Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv143","article-title":"Digoxin-associated mortality: a systematic review and meta-analysis of the literature","volume":"36","author":"Vamos","year":"2015","journal-title":"Eur Heart J"},{"key":"B19","doi-asserted-by":"publisher","first-page":"106331","DOI":"10.1016\/j.intimp.2020.106331","article-title":"Cardiac glycoside digoxin ameliorates pro-inflammatory cytokines in PB MCs of rheumatoid arthritis patients in vitro","volume":"82","author":"Saeed","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000001096","article-title":"Digoxin attenuates murine experimental colitis by downregulating th17- related cytokines","volume":"23","author":"Tani","year":"2017","journal-title":"Inflammation Bowel Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsps.2022.01.007","article-title":"Digoxin mitigates diethylnitrosamine-induced acute liver injury in mice via limiting production of inflammatory mediators","volume":"30","author":"Shaker","year":"2022","journal-title":"Saudi Pharm J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221380","article-title":"Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis","volume":"81","author":"Wang","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.joca.2022.03.011","article-title":"Alarmins S100A8\/A9 promote intervertebral disc degeneration and inflam mation-related pain in a rat model through toll-like receptor-4 and ac tivation of the NF-\u03baB signaling pathway","volume":"30","author":"Zheng","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.21935","article-title":"Repurposing of digoxin in pain and inflammation: An evidence-based stu dy","volume":"83","author":"Patel","year":"2022","journal-title":"Drug Dev Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2010.08.013","article-title":"The effect of needle size inducing degeneration in the rat caudal disc: evaluation using radiograph, magnetic resonance imaging, histology, and immunohistochemistry","volume":"10","author":"Keorochana","year":"2010","journal-title":"Spine J"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e31817c64a9","article-title":"A simple disc degeneration model induced by percutaneous needle punctu re in the rat tail","volume":"33","author":"Han","year":"2008","journal-title":"Spine"},{"key":"B27","first-page":"194","article-title":"Cytokine networking of chondrocyte dedifferentiation in vitro and its implications for cell-based cartilage therapy","volume":"7","author":"Duan","year":"2015","journal-title":"Am J Transl Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.02.027","article-title":"The PI3K\/AKT\/mTOR signaling pathway in osteoarthritis: a narrative review","volume":"28","author":"Sun","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"key":"B29","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13578-022-00792-9","article-title":"LRP4 is required for the olfactory association task in the piriform co rtex","volume":"12","author":"Yan","year":"2022","journal-title":"Cell Biosci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s13578-021-00619-z","article-title":"Synapse-specific Lrp4 mRNA enrichment requires Lrp4\/MuSK signaling, mu scle activity and Wnt non-canonical pathway","volume":"11","author":"Jing","year":"2021","journal-title":"Cell Biosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/art.34347","article-title":"A systematic review of the global prevalence of low back pain","volume":"64","author":"Hoy","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B32","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/nyas.13551","article-title":"Inflammatory biomarkers of low back pain and disc degeneration: a revi ew","volume":"1410","author":"Khan","year":"2017","journal-title":"Ann NY Acad Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202101483","article-title":"Local delivery of senolytic drug inhibits intervertebral disc degenera tion and restores intervertebral disc structure","volume":"11","author":"Lim","year":"2021","journal-title":"Adv Healthc Mater"},{"key":"B35","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3390\/cells11030394","article-title":"Causes of and molecular targets for the treatment of intervertebral di sc degeneration: A review","volume":"11","author":"Ohnishi","year":"2022","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.joca.2021.02.204","article-title":"Roles of NLRP3 inflammasome in intervertebral disc degeneration","volume":"29","author":"Chao-Yang","year":"2021","journal-title":"Osteoarthritis Cartilage"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2958584","DOI":"10.1155\/2021\/2958584","article-title":"CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via th e MAPK\/NF-\u03baB Signaling Pathways during Intervertebral Disc Dege neration","author":"Sun","year":"2021","journal-title":"Oxid Med Cell Longevity"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.3390\/ijms23031715","article-title":"The proteolysis of ECM in intervertebral disc degeneration","volume":"23","author":"Liang","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s12951-021-00991-5","article-title":"Injectable exosome-functionalized extracellular matrix hydrogel for me tabolism balance and pyroptosis regulation in intervertebral disc dege neration","volume":"19","author":"Xing","year":"2021","journal-title":"J Nanobiotechnol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13057","article-title":"NF-\u03baB signalling pathways in nucleus pulposus cell function and interv ertebral disc degeneration","volume":"54","author":"Zhang","year":"2021","journal-title":"Cell Prolif"},{"key":"B41","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s13075-022-02804-y","article-title":"Excessive mechanical stress-induced intervertebral disc degeneration is related to Piezo1 overexpression triggering the imbalance of autophagy\/apoptosis in human nucleus pulpous","volume":"24","author":"Shi","year":"2022","journal-title":"Arthritis Res Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.01.005","article-title":"Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration","volume":"117","author":"Xu","year":"2017","journal-title":"Pharmacol Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1251517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T07:33:09Z","timestamp":1695108789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1251517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,18]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2023.1251517"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1251517","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,18]]},"article-number":"1251517"}}