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RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs
BACKGROUND: Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent end...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487042/ https://www.ncbi.nlm.nih.gov/pubmed/31029152 http://dx.doi.org/10.1186/s12967-019-1886-3 |
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author | Qiu, Xubin Zhuang, Ming Lu, Ziwen Liu, Zhiwei Cheng, Dong Zhu, Chenlei Liu, Jinbo |
author_facet | Qiu, Xubin Zhuang, Ming Lu, Ziwen Liu, Zhiwei Cheng, Dong Zhu, Chenlei Liu, Jinbo |
author_sort | Qiu, Xubin |
collection | PubMed |
description | BACKGROUND: Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration. METHODS: In this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients’ normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo. RESULTS: RIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients’ degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1. CONCLUSIONS: These results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-019-1886-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6487042 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64870422019-05-06 RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs Qiu, Xubin Zhuang, Ming Lu, Ziwen Liu, Zhiwei Cheng, Dong Zhu, Chenlei Liu, Jinbo J Transl Med Research BACKGROUND: Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration. METHODS: In this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients’ normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo. RESULTS: RIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients’ degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1. CONCLUSIONS: These results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-019-1886-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-27 /pmc/articles/PMC6487042/ /pubmed/31029152 http://dx.doi.org/10.1186/s12967-019-1886-3 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Qiu, Xubin Zhuang, Ming Lu, Ziwen Liu, Zhiwei Cheng, Dong Zhu, Chenlei Liu, Jinbo RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title | RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title_full | RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title_fullStr | RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title_full_unstemmed | RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title_short | RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
title_sort | ripk1 suppresses apoptosis mediated by tnf and caspase-3 in intervertebral discs |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487042/ https://www.ncbi.nlm.nih.gov/pubmed/31029152 http://dx.doi.org/10.1186/s12967-019-1886-3 |
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