Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway
Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as...
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| Format: | Article |
| Language: | English |
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The British Editorial Society of Bone & Joint Surgery
2024-03-01
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| Series: | Bone & Joint Research |
| Subjects: | |
| Online Access: | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.133.BJR-2023-0250.R1 |
| _version_ | 1797228934846218240 |
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| author | Jingting Xu Zhaoxuan Ruan Zhou Guo Liangcai Hou Genchun Wang Zehang Zheng Xiong Zhang Haigang Liu Kai Sun Fengjing Guo |
| author_facet | Jingting Xu Zhaoxuan Ruan Zhou Guo Liangcai Hou Genchun Wang Zehang Zheng Xiong Zhang Haigang Liu Kai Sun Fengjing Guo |
| author_sort | Jingting Xu |
| collection | DOAJ |
| description | Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1β (IL-1β) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1β and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1β and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA. Cite this article: Bone Joint Res 2024;13(3):110–123. |
| first_indexed | 2024-04-24T15:04:35Z |
| format | Article |
| id | doaj.art-bd074a90b237484faa68f1ebdcacbd21 |
| institution | Directory Open Access Journal |
| issn | 2046-3758 |
| language | English |
| last_indexed | 2024-04-24T15:04:35Z |
| publishDate | 2024-03-01 |
| publisher | The British Editorial Society of Bone & Joint Surgery |
| record_format | Article |
| series | Bone & Joint Research |
| spelling | doaj.art-bd074a90b237484faa68f1ebdcacbd212024-04-02T13:47:14ZengThe British Editorial Society of Bone & Joint SurgeryBone & Joint Research2046-37582024-03-0113311012310.1302/2046-3758.133.BJR-2023-0250.R1Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathwayJingting Xu0https://orcid.org/0000-0003-2554-615XZhaoxuan Ruan1https://orcid.org/0009-0006-4652-1735Zhou Guo2https://orcid.org/0000-0001-9043-9196Liangcai Hou3https://orcid.org/0000-0003-1368-9823Genchun Wang4Zehang Zheng5Xiong Zhang6Haigang Liu7Kai Sun8Fengjing Guo9https://orcid.org/0000-0002-5968-4836Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaAims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1β (IL-1β) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1β and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1β and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA. Cite this article: Bone Joint Res 2024;13(3):110–123.https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.133.BJR-2023-0250.R1osteoarthritischondrocyteferroptosisinflammationchondrocytescollagen iiintra-articular injectionlipidcollageninterleukin-1βrnareactive oxygen speciesdestabilization of the medial meniscus (dmm) surgery |
| spellingShingle | Jingting Xu Zhaoxuan Ruan Zhou Guo Liangcai Hou Genchun Wang Zehang Zheng Xiong Zhang Haigang Liu Kai Sun Fengjing Guo Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway Bone & Joint Research osteoarthritis chondrocyte ferroptosis inflammation chondrocytes collagen ii intra-articular injection lipid collagen interleukin-1β rna reactive oxygen species destabilization of the medial meniscus (dmm) surgery |
| title | Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway |
| title_full | Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway |
| title_fullStr | Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway |
| title_full_unstemmed | Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway |
| title_short | Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway |
| title_sort | inhibition of sat1 alleviates chondrocyte inflammation and ferroptosis by repressing alox15 expression and activating the nrf2 pathway |
| topic | osteoarthritis chondrocyte ferroptosis inflammation chondrocytes collagen ii intra-articular injection lipid collagen interleukin-1β rna reactive oxygen species destabilization of the medial meniscus (dmm) surgery |
| url | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.133.BJR-2023-0250.R1 |
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