{"title":"抑制 SAT1 可抑制 ALOX15 的表达并激活 Nrf2 通路,从而减轻软骨细胞的炎症和铁变态反应。","authors":"Jingting Xu, Zhaoxuan Ruan, Zhou Guo, Liangcai Hou, Genchun Wang, Zehang Zheng, Xiong Zhang, Haigang Liu, Kai Sun, Fengjing Guo","doi":"10.1302/2046-3758.133.BJR-2023-0250.R1","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":9074,"journal":{"name":"Bone & Joint Research","volume":"13 3","pages":"110-123"},"PeriodicalIF":4.7000,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917474/pdf/","citationCount":"0","resultStr":"{\"title\":\"Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway.\",\"authors\":\"Jingting Xu, Zhaoxuan Ruan, Zhou Guo, Liangcai Hou, Genchun Wang, Zehang Zheng, Xiong Zhang, Haigang Liu, Kai Sun, Fengjing Guo\",\"doi\":\"10.1302/2046-3758.133.BJR-2023-0250.R1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":9074,\"journal\":{\"name\":\"Bone & Joint Research\",\"volume\":\"13 3\",\"pages\":\"110-123\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-03-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917474/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bone & Joint Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1302/2046-3758.133.BJR-2023-0250.R1\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone & Joint Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1302/2046-3758.133.BJR-2023-0250.R1","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0
摘要
目的:骨关节炎(OA)是人体关节最常见的慢性病变。其发病机制复杂,涉及生理和机械因素。在以往的研究中,我们发现铁蜕变与 OA 密切相关,而 Sat1 在软骨细胞铁蜕变和 OA 中的作用及其内在机制尚不清楚:本研究用白细胞介素-1β(IL-1β)模拟炎症,用Erastin模拟体外软骨细胞铁沉着。我们使用小干扰 RNA(siRNA)敲除了精胺/精胺 N1-乙酰转移酶 1(Sat1)和花生四烯酸 15-脂氧合酶(Alox15),并检测了与损伤相关的事件,包括炎症、铁败坏和软骨细胞的氧化应激。此外,还建立了手术诱导的内侧半月板失稳(DMM)小鼠模型,以研究抑制 Sat1 在 OA 进展中的作用:结果表明,抑制Sat1的表达可减少IL-1β和Erastin诱导的炎症、铁变态反应、活性氧(ROS)水平和脂质-ROS积累。敲除 Sat1 可促进核因子-E2 相关因子 2(Nrf2)信号的传递。此外,敲除 Alox15 可减轻 IL-1β 诱导的炎症相关蛋白表达和 Erastin 诱导的铁突变相关蛋白表达。此外,敲除 Nrf2 可以逆转这些蛋白表达的改变。最后,关节内注射 Sat1 抑制剂乙酸二咪唑(DA)可增强 II 型胶原(胶原 II),增加 Sat1 和 Alox15 的表达:我们的研究结果表明,抑制 Sat1 可通过下调 Alox15 激活 Nrf2 系统来缓解软骨细胞的铁突变和炎症,并延缓 OA 的进展。这些研究结果表明,Sat1 为研究和治疗 OA 提供了一种新方法。
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 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.