The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis
Osteoarthritis (OA) is a degenerative or posttraumatic condition of the joints. In OA chondrocytes, Nrf2 functions as a stress response regulator with antioxidant and anti-inflammatory effects. This study aims to investigate the role of Nrf2 and its downstream pathway in the development of osteoarth...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2023-05-01
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| Series: | Acta Biochimica et Biophysica Sinica |
| Subjects: | |
| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2023078 |
| _version_ | 1797635806706270208 |
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| author | Li Wenzhao Tao Cheng Mao Minzhi Zhu Kewei |
| author_facet | Li Wenzhao Tao Cheng Mao Minzhi Zhu Kewei |
| author_sort | Li Wenzhao |
| collection | DOAJ |
| description | Osteoarthritis (OA) is a degenerative or posttraumatic condition of the joints. In OA chondrocytes, Nrf2 functions as a stress response regulator with antioxidant and anti-inflammatory effects. This study aims to investigate the role of Nrf2 and its downstream pathway in the development of osteoarthritis. IL-1β treatment suppresses Nrf2, aggrecan, and COL2A1 levels and cell viability but promotes apoptosis in chondrocytes. IL-1β stimulation induces cell apoptosis, upregulates the mRNA expression of inflammatory factors, decreases aggrecan, COL2A1, and Bcl-2 levels but increases ADAMTS-5, ADAMTS-4, MMP13, cleaved caspase 3, and BAX levels, and promotes p65 phosphorylation. Nrf2 overexpression exerts opposite effects on IL-1β-treated chondrocytes, as demonstrated by the significant attenuation of IL-1β-induced changes in chondrocytes. By binding to the HMGB1 promoter region, Nrf2 suppresses HMGB1 expression. Similar to Nrf2 overexpression, HMGB1 knockdown also attenuates IL-1β-induced changes in chondrocytes. Notably, under IL-1β stimulation, the effects of Nrf2 overexpression or tert-butylhydroquinone (TBHQ, an activator of Nrf2) on apoptosis, inflammatory factor expression, ECM and apoptosis, and NF-κB pathway activity in chondrocytes are remarkably reversed by HMGB1 overexpression or recombinant HMGB1 (rHMGB1). Similarly, rHMGB1 could partially counteract the curative effect of TBHQ on OA damage in mice. In OA cartilage tissue samples, the level of Nrf2 is lower, while the levels of HMGB1, apoptotic, and inflammatory factors are increased compared to normal cartilage tissue samples. In conclusion, for the first time, the Nrf2/HMGB1 axis was found to modulate apoptosis, ECM degradation, inflammation and activation of NF-κB signaling in chondrocytes and OA mice. |
| first_indexed | 2024-03-11T12:26:36Z |
| format | Article |
| id | doaj.art-4dbe9219712f4776943e4c6837ddf4ed |
| institution | Directory Open Access Journal |
| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:26:36Z |
| publishDate | 2023-05-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-4dbe9219712f4776943e4c6837ddf4ed2023-11-06T08:47:36ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452023-05-015581883010.3724/abbs.202307820d259ccThe Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritisLi Wenzhao0Tao Cheng1Mao Minzhi2Zhu Kewei3[][][][]Osteoarthritis (OA) is a degenerative or posttraumatic condition of the joints. In OA chondrocytes, Nrf2 functions as a stress response regulator with antioxidant and anti-inflammatory effects. This study aims to investigate the role of Nrf2 and its downstream pathway in the development of osteoarthritis. IL-1β treatment suppresses Nrf2, aggrecan, and COL2A1 levels and cell viability but promotes apoptosis in chondrocytes. IL-1β stimulation induces cell apoptosis, upregulates the mRNA expression of inflammatory factors, decreases aggrecan, COL2A1, and Bcl-2 levels but increases ADAMTS-5, ADAMTS-4, MMP13, cleaved caspase 3, and BAX levels, and promotes p65 phosphorylation. Nrf2 overexpression exerts opposite effects on IL-1β-treated chondrocytes, as demonstrated by the significant attenuation of IL-1β-induced changes in chondrocytes. By binding to the HMGB1 promoter region, Nrf2 suppresses HMGB1 expression. Similar to Nrf2 overexpression, HMGB1 knockdown also attenuates IL-1β-induced changes in chondrocytes. Notably, under IL-1β stimulation, the effects of Nrf2 overexpression or tert-butylhydroquinone (TBHQ, an activator of Nrf2) on apoptosis, inflammatory factor expression, ECM and apoptosis, and NF-κB pathway activity in chondrocytes are remarkably reversed by HMGB1 overexpression or recombinant HMGB1 (rHMGB1). Similarly, rHMGB1 could partially counteract the curative effect of TBHQ on OA damage in mice. In OA cartilage tissue samples, the level of Nrf2 is lower, while the levels of HMGB1, apoptotic, and inflammatory factors are increased compared to normal cartilage tissue samples. In conclusion, for the first time, the Nrf2/HMGB1 axis was found to modulate apoptosis, ECM degradation, inflammation and activation of NF-κB signaling in chondrocytes and OA mice. https://www.sciengine.com/doi/10.3724/abbs.2023078osteoarthritis (OA)cartilage chondrocyteextracellular matrix (ECM)Nrf2HMGB1 |
| spellingShingle | Li Wenzhao Tao Cheng Mao Minzhi Zhu Kewei The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis Acta Biochimica et Biophysica Sinica osteoarthritis (OA) cartilage chondrocyte extracellular matrix (ECM) Nrf2 HMGB1 |
| title | The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| title_full | The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| title_fullStr | The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| title_full_unstemmed | The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| title_short | The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| title_sort | nrf2 hmgb1 nf κb axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis |
| topic | osteoarthritis (OA) cartilage chondrocyte extracellular matrix (ECM) Nrf2 HMGB1 |
| url | https://www.sciengine.com/doi/10.3724/abbs.2023078 |
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