Targeting hexokinase-2 in rheumatoid arthritis

靶向己糖激酶 2 治疗类风湿性关节炎

基本信息

批准号：
10190836
负责人：
Monica Guma
金额：
$ 33.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190836
关键词：
Address Adult Affect Apoptosis Arthritis Binding Cartilage Cells Cellular Metabolic Process Color Combined Modality Therapy Confocal Microscopy Cytosol Data Development Disease Endoplasmic Reticulum Enzymes Fibroblasts Glucose Transporter Glycolysis Glycolysis Inhibition Growth Hexokinase 2 Homeostasis Hypoxia Immunosuppression Impairment In Vitro Inflammation Inflammatory Inflammatory Arthritis Injections Interleukin-6 Intra-Articular Injections Joints Knee Lesion Macrophage Activation Membrane Membrane Proteins Metabolic Metabolism Miconazole Mitochondria Molecular Mus Normal Cell Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Play Population Process Protein Isoforms Rheumatism Rheumatoid Arthritis Risk Role Sampling Severities Signal Pathway Stromal Cells Synovial Cell Synovial Fluid Synovial Membrane Synovitis Testing Therapeutic Thick Tissues Up-Regulation Voltage-Dependent Anion Channel Work adenoviral-mediated arthropathies bone bone cell cell motility cell type extracellular glucose metabolism hexokinase improved in vivo insight joint destruction joint inflammation knock-down macrophage migration mutant novel novel therapeutics overexpression peptide drug public health relevance voltage-dependent anion channel 2

项目摘要

ABSTRACT Targeting Hexokinase 2 in Rheumatoid Arthritis (changes are underlined) Hexokinases (HKs) catalyze the first committed step in glucose metabolism. HK2 constitutes the principal inducible isoform and has a restricted distribution of expression in normal adult tissues. Cell populations with increased glycolysis and HK2 expression have a powerful growth advantage. HK2 localizes also at mitochondria, and its interaction increases glucose metabolism and protects mitochondria against apoptosis. Thus, mitochondrial HK2 translocation promotes an activated phenotype in several cell types. Fibroblast like synoviocytes (FLS) and macrophages (MO) are a key component of rheumatoid arthritis (RA) inflamed synovium and contribute to the initiation and perpetuation of destructive joint inflammation. FLS from patients with RA display unique aggressive features, which are autonomous and vertically transmitted. MO are also critical in the pathogenesis of RA. The increase in the number of sublining MO in the synovium is an early hallmark of active rheumatic disease, and high numbers of MO are a prominent feature of inflammatory lesions. Of note, a critical role of glucose metabolism in both activated FLS and MO, have been highlighted by our recent work among others. Our preliminary data demonstrate that while HK1 expression is expressed in both OA and RA synovium, HK2 expression co-localizes with MO and FLS markers, and is only observed in RA and not in OA synovial samples. We also show that HK2 regulates key FLS function as HK2 knockdown impaired FLS invasion. Conversely, HK2 overexpression increases FLS invasion and migration rate. Of note, lactate and PLOD2, which are involved in cell migration and invasion, are upregulated after HK2 expression. Up-regulation of extracellular lactate also suggests a metabolic shift towards accelerated glycolytic metabolism. An HK2 mutant lacking its mitochondrial-binding motif (HK2ΔN) reversed the invasive phenotype. In MO, a peptide that dissociates HK2 from mitochondria, impaired IL-6 secretion. Importantly, adenovirus-mediated expression of HK2 in the knee by intra-articular injection induced synovial thickness, which was much less evident when HK2ΔN was intra-articular injected. Finally, HK2F/F-Col1a1 mice, which deletes HK2 in FLS among other non- hematopoietic cells, and treatment with clotrimazole, which dissociated HK2 from mitochondria, significantly decreased arthritis severity. Thus, we will test the hypothesis that mitochondrial HK2 is key regulator of FLS phenotype and MO activation, which contributes to joint destruction in RA. The identification of HK2, an isoform-specific contributor to elevated cell glucose metabolism in RA synovial tissue offers a safer approach than global glycolysis inhibition. HK2 could be selectively targeted without compromising systemic homeostasis or corresponding metabolic function in normal cells as a novel additional approach for combination therapy in RA joint disease independent of systemic immunosuppression.

抽象的靶向类风湿关节炎中的己糖激酶2（强调的变化）己糖酶（HKS）催化了葡萄糖代谢的第一步。 HK2构成校长可诱导的同工型，在正常成人组织中表达分布有限。细胞群体糖酵解和HK2表达的增加具有强大的生长优势。 HK2也本地化线粒体及其相互作用会增加葡萄糖代谢，并保护线粒体免受凋亡。这，线粒体HK2易位促进了几种细胞类型的活化表型。像滑膜细胞（FLS）和巨噬细胞（MO）之类的成纤维细胞是类风湿关节炎（RA）的关键组成部分发炎的滑膜并有助于破坏性关节感染的主动性和永久性。来自具有RA的患者表现出独特的侵略性特征，这些特征是自主且垂直传播的。 mo是 RA的发病机理也很重要。 Synovium中升华MO的数量的增加是早期活动风湿病和大量MO的标志是炎症的重要特征病变。值得注意的是，葡萄糖代谢在激活的FL和MO中的关键作用已突出显示我们最近的工作。我们的初步数据表明，虽然HK1表达在OA和RA Synovium中均表达，但HK2 表达式与MO和FLS标记共定位，仅在RA中观察到，而不是在OA滑膜中观察到样品。我们还表明，HK2调节关键FLS功能是HK2敲低的FLS入侵。相反，HK2的过表达增加了FL的侵袭和迁移率。值得注意的是，裂缝和plod2，与细胞迁移和侵袭有关的，在HK2表达后会更新。上调细胞外缝隙还表明，代谢转向加速糖酵解代谢。 HK2突变体缺乏其线粒体结合基序（HK2ΔN）逆转了侵入性表型。在莫，一个胡椒从线粒体中分离HK2，IL-6分泌受损。重要的是，腺病毒介导的表达通过关节内注射诱导的滑膜厚度，膝盖中的HK2在 HK2ΔN被关节内注射。最后，HK2F/f-Col1a1小鼠，在其他非 - 造血细胞以及用线粒体解离HK2的氯咪唑的治疗关节炎的严重程度降低。这是我们将测试线粒体HK2是FLS的关键调节剂的假设表型和MO激活，有助于RA的关节破坏。识别HK2，一个 RA滑膜组织中升高细胞葡萄糖代谢升高的同工型特异性贡献者可提供更安全的方法比全球糖酵解抑制作用。 HK2可以选择性地靶向而不妥协正常细胞中的全身稳态或相应的代谢功能作为新颖的额外与全身免疫抑制无关的RA联合疾病联合疗法的方法。