CPT1A-Mediated Fatty Acid Oxidation Promotes Precursor Osteoclast Fusion in Rheumatoid Arthritis.
CPT1A-Mediated Fatty Acid Oxidation Promotes Precursor Osteoclast Fusion in Rheumatoid Arthritis.
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DOI：
10.3389/fimmu.2022.838664
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发表时间：
2022
影响因子：
7.3
通讯作者：
Shao L
中科院分区：
文献类型：
--
作者：
Huang Z;Luo R;Yang L;Chen H;Zhang X;Han J;Wang H;Zhou Z;Wang Z;Shao L
在类风湿性关节炎(RA)患者中，破骨细胞的过度产生导致骨破坏是公认的。然而，关于破骨细胞前体(OCP)在RA中的代谢功能障碍，人们知之甚少。在这里，我们表明，增加脂肪酸氧化(FAO)诱导OCP融合。肉碱棕榈酰基转移酶IA(CPT1A)在RA患者的线粒体中表达上调，CPT1A对肉碱转运起重要作用，并参与粮农组织在线粒体中的表达。这种代谢变化通过增强转录因子CCAAT/增强子结合蛋白β(C/eBPβ)与cltA和cltc启动子的结合，进一步增加了cltc和cltA的表达。这驱动了依赖于笼蛋白的内吞途径，从而削弱了细胞膜上的融合受体，并有助于增加足体结构的形成。本研究揭示了FAO代谢参与类风湿关节炎关节破坏的新机制，为开发抗类风湿关节炎患者骨破坏药物提供了新的治疗方向。
The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA.