Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling

BackgroundIntervertebral 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-i...

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Main Authors: Qunbo Meng, Kaiwen Liu, Zhenchuan Liu, Jinbo Liu, Ziyu Tian, Shanshan Qin, Jianlu Wei, Lei Cheng
Format: Article
Language:English
Published: Frontiers Media S.A. 2023-09-01
Series:Frontiers in Immunology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251517/full
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author Qunbo Meng
Qunbo Meng
Kaiwen Liu
Kaiwen Liu
Zhenchuan Liu
Zhenchuan Liu
Jinbo Liu
Jinbo Liu
Ziyu Tian
Ziyu Tian
Shanshan Qin
Jianlu Wei
Jianlu Wei
Lei Cheng
Lei Cheng
author_facet Qunbo Meng
Qunbo Meng
Kaiwen Liu
Kaiwen Liu
Zhenchuan Liu
Zhenchuan Liu
Jinbo Liu
Jinbo Liu
Ziyu Tian
Ziyu Tian
Shanshan Qin
Jianlu Wei
Jianlu Wei
Lei Cheng
Lei Cheng
author_sort Qunbo Meng
collection DOAJ
description BackgroundIntervertebral 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.ObjectiveThis 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.MethodsWe exploited a rat needle model to investigate digoxin’s role in intervertebral disc degeneration in vivo. 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&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-α-induced inflammatory effects in vitro. 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.ResultsDigoxin 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-α-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.ConclusionThese 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.
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spelling doaj.art-0fd9a343eb8944b9a3567fc9038920342023-09-19T07:33:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12515171251517Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signalingQunbo Meng0Qunbo Meng1Kaiwen Liu2Kaiwen Liu3Zhenchuan Liu4Zhenchuan Liu5Jinbo Liu6Jinbo Liu7Ziyu Tian8Ziyu Tian9Shanshan Qin10Jianlu Wei11Jianlu Wei12Lei Cheng13Lei Cheng14Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University, Shandong University, Jinan, Shandong, ChinaDepartment of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University, Shandong University, Jinan, Shandong, ChinaDepartment of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University, Shandong University, Jinan, Shandong, ChinaDepartment of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University, Shandong University, Jinan, Shandong, ChinaDepartment of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong, ChinaDepartment of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong, ChinaDepartment of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University Spine and Spinal Cord Disease Research Center-International Chinese Musculoskeletal Research Society (ICMRS) Collaborating Center for Orthopaedic Translational Research, Shandong University, Jinan, Shandong, ChinaDepartment of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaQilu Hospital of Shandong University Spine and Spinal Cord Disease Research Center-International Chinese Musculoskeletal Research Society (ICMRS) Collaborating Center for Orthopaedic Translational Research, Shandong University, Jinan, Shandong, ChinaBackgroundIntervertebral 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.ObjectiveThis 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.MethodsWe exploited a rat needle model to investigate digoxin’s role in intervertebral disc degeneration in vivo. 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&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-α-induced inflammatory effects in vitro. 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.ResultsDigoxin 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-α-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.ConclusionThese 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251517/fulldigoxinintervertebral disc degenerationTNFLRP4inflammation
spellingShingle Qunbo Meng
Qunbo Meng
Kaiwen Liu
Kaiwen Liu
Zhenchuan Liu
Zhenchuan Liu
Jinbo Liu
Jinbo Liu
Ziyu Tian
Ziyu Tian
Shanshan Qin
Jianlu Wei
Jianlu Wei
Lei Cheng
Lei Cheng
Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
Frontiers in Immunology
digoxin
intervertebral disc degeneration
TNF
LRP4
inflammation
title Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
title_full Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
title_fullStr Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
title_full_unstemmed Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
title_short Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling
title_sort digoxin protects against intervertebral disc degeneration via tnf nf κb and lrp4 signaling
topic digoxin
intervertebral disc degeneration
TNF
LRP4
inflammation
url https://www.frontiersin.org/articles/10.3389/fimmu.2023.1251517/full
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