LPCAT3的甲基化调控通过调节ACSL4抑制软骨细胞铁凋亡改善骨关节炎

IF 1.5 4区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Critical Reviews in Eukaryotic Gene Expression Pub Date : 2024-01-01 DOI:10.1615/CritRevEukaryotGeneExpr.2023049244
Kaken Habaxi, Wei Wang, Maimaitiaili Taximaimaiti, Li Wang
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引用次数: 0

摘要

随着中国老龄化人口的不断增加,膝骨关节炎的发病率预计将逐年上升。因此,我们开展了一项研究,探讨LPCAT3在骨关节炎中的关键作用及其内在机制。我们采集了本院正常志愿者(12 人)和骨关节炎患者(12 人)的样本。结果发现,骨关节炎患者 LPCAT3 mRNA 表达减少,且与 IL-1β mRNA 表达呈正相关。在小鼠模型中,发现 LPCAT3 mRNA 和蛋白表达均受到抑制。此外,在体外模型中,特异性 m6A 抗体通过 si-METTL3 抑制了 LPCAT3 mRNA 的富集水平。Si-METTL3 还降低了体外模型中 LPCAT3 mRNA 的稳定性。在小鼠模型中,发现抑制 LPCAT3 会加重骨关节炎。此外,LPCAT3 还能减轻体外模型中的炎症反应。研究还观察到,LPCAT3 通过抑制线粒体损伤减少了软骨细胞的铁变态反应。研究发现,LPCAT3 蛋白与 ACSL4 蛋白相互作用,其上调可抑制体外模型中 ACSL4 的表达。在体外模型中,ACSL4 被确定为 LPCAT3 抑制线粒体损伤的靶点。总之,本研究证明 LPCAT3 可通过调节 ACSL4 来抑制软骨细胞的铁突变,从而改善骨关节炎,为骨关节炎的治疗提供了一个新靶点。
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Methylation Regulation of LPCAT3 Improves Osteoarthritis by Regulating ACSL4 to Inhibit Chondrocyte Ferroptosis.

With the increasing aging population in China, the incidence rate of knee osteoarthritis is expected to rise annually. Therefore, we conducted a study to investigate the crucial role of LPCAT3 in osteoarthritis and its underlying mechanisms. We collected samples from normal volunteers (n = 12) and patients with osteoarthritis (n = 12) at our hospital. It was observed that LPCAT3 mRNA expression was reduced and positively correlated with IL-1β mRNA expression in patients with osteoarthritis. In a mouse model, LPCAT3 mRNA and protein expression were found to be suppressed. Furthermore, in an in vitro model, the enrichment level of LPCAT3 mRNA was inhibited by a specific m6A antibody through si-METTL3. Si-METTL3 also reduced the stability of LPCAT3 mRNA in the in vitro model. The inhibition of LPCAT3 was found to exacerbate osteoarthritis in the mouse model. Additionally, LPCAT3 was shown to reduce inflammation in the in vitro model. It was also observed that LPCAT3 reduced chondrocyte ferroptosis by inhibiting mitochondrial damage. LPCAT3 protein was found to interact with ACSL4 protein, and its up-regulation suppressed ACSL4 expression in the in vitro model. ACSL4 was identified as a target of LPCAT3 for suppressing mitochondrial damage in the in vitro model. In conclusion, this study demonstrates that LPCAT3 improves osteoarthritis by regulating ACSL4 to inhibit chondrocyte ferroptosis, thus providing a novel target for the treatment of osteoarthritis.

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来源期刊
Critical Reviews in Eukaryotic Gene Expression
Critical Reviews in Eukaryotic Gene Expression 生物-生物工程与应用微生物
CiteScore
2.70
自引率
0.00%
发文量
67
审稿时长
1 months
期刊介绍: Critical ReviewsTM in Eukaryotic Gene Expression presents timely concepts and experimental approaches that are contributing to rapid advances in our mechanistic understanding of gene regulation, organization, and structure within the contexts of biological control and the diagnosis/treatment of disease. The journal provides in-depth critical reviews, on well-defined topics of immediate interest, written by recognized specialists in the field. Extensive literature citations provide a comprehensive information resource. Reviews are developed from an historical perspective and suggest directions that can be anticipated. Strengths as well as limitations of methodologies and experimental strategies are considered.
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