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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Journal of translational medicine - 17(2019), 1 vom: 27. Apr., Seite 135 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qiu, Xubin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.04.2020 Date Revised 29.04.2020 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12967-019-1886-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM296490873 |
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| 041 | |a eng | ||
| 100 | 1 | |a Qiu, Xubin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RIPK1 suppresses apoptosis mediated by TNF and caspase-3 in intervertebral discs |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 29.04.2020 | ||
| 500 | |a Date Revised 29.04.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Degeneration | |
| 650 | 4 | |a Intervertebral disc | |
| 650 | 4 | |a RIPK1 | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
| 650 | 7 | |a RIPK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Receptor-Interacting Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Caspase 3 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 700 | 1 | |a Zhuang, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Ziwen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Chenlei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jinbo |e verfasserin |4 aut | |
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