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      Ghrelin protects against nucleus pulposus degeneration through inhibition of NF-κB signaling pathway and activation of Akt signaling pathway

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          Abstract

          The objective of the present study was to examine the potential role of ghrelin in degeneration of nucleus pulposus (NP). Lower expression levels of ghrelin were found in human NP cells stimulated with interleukin-1β (IL-1β). Moreover, exogenous ghrelin suppressed IL-1β induced degeneration and inflammation associated biomarkers in human NP cells, including matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs-5, tumor necrosis factor-α and iNOS, which was possibly mediated by antagonization of NF-κB signaling. Moreover, ghrelin enhanced production of critical extracellular matrix of NP cells, including collagen 2, aggrecan, and Sox-9 in NP cells. Ghrelin also promoted NP tissue regeneration in a rabbit IVD degeneration model, which seems to be associated with growth hormone secretagogue receptor. Additionally, the protective role of ghrelin in anabolism potentially relies on activation of Akt signaling pathway. Taken together, ghrelin may represent a molecular target for prevention and treatment of intervertebral disc degeneration.

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          The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.

          The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.
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            Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

            In this Review, the authors discuss the function of the TNF and TNF receptor superfamily, their role in rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus, and how current knowledge is being translated into potential disease therapies.
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              Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB.

              We investigated TNF-α and IL-1β regulation of ADAMTS-4 expression in nucleus pulposus (NP) cells and its role in aggrecan degradation. Real-time quantitative RT-PCR, Western blotting, and transient transfections with rat NP cells and lentiviral silencing with human NP cells were performed to determine the roles of MAPK and NF-κB in cytokine-mediated ADAMTS-4 expression and function. ADAMTS4 expression and promoter activity increased in NP cells after TNF-α and IL-1β treatment. Treatment of cells with MAPK and NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS4 mRNA and protein expression. Although ERK1, p38α, p38β2, and p38γ were involved in induction, ERK2 and p38δ played no role in TNF-α-dependent promoter activity. The inductive effect of p65 on ADAMTS4 promoter was confirmed through gain and loss-of-function studies. Cotransfection of p50 completely blocked p65-mediated induction. Lentiviral transduction with shRNA plasmids shp65, shp52, shIKK-α, and shIKK-β significantly decreased TNF-α-dependent increase in ADAMTS-4 and -5 levels and aggrecan degradation. Silencing of either ADAMTS-4 or -5 resulted in reduction in TNF-α-dependent aggrecan degradation in NP cells. By controlling activation of MAPK and NF-κB signaling, TNF-α and IL-1β modulate expression of ADAMTS-4 in NP cells. To our knowledge, this is the first study to show nonredundant contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells in vitro. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                3 November 2017
                31 July 2017
                : 8
                : 54
                : 91887-91901
                Affiliations
                1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P. R. China
                2 Department of Gynaecology and Obstetrics, Jinan Central Hospital, Shandong University, Jinan, Shandong 250012, P. R. China
                3 Medical School of Shandong University, Jinan, Shandong 250012, P. R. China
                4 Department of Orthopaedics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P. R. China
                5 Department of Oral and Maxillofacial Surgery and Institute of Dental Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P. R. China
                Author notes
                Article
                19695
                10.18632/oncotarget.19695
                5696149
                29190883
                f0edba4d-2f15-4d5c-b120-4028eece8bae
                Copyright: © 2017 Li et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 30 January 2017
                : 27 June 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                nucleus pulposus,il-1β,ghrelin,nf-κb signaling,akt signaling
                Oncology & Radiotherapy
                nucleus pulposus, il-1β, ghrelin, nf-κb signaling, akt signaling

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