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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：
10633710
负责人：
Monica Guma
金额：
$ 12万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10633710
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.

摘要

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis?

DOI：
10.3390/jcm8050753
发表时间：
2019-05
期刊：
Journal of Clinical Medicine
影响因子：
3.9
作者：
E. Sanchez-Lopez;An-Chieh Cheng;M. Guma
通讯作者：
E. Sanchez-Lopez;An-Chieh Cheng;M. Guma

Molecular imaging for evaluation of synovitis associated with osteoarthritis: a narrative review.

DOI：
10.1186/s13075-023-03258-6
发表时间：
2024-01-16
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
通讯作者：

Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.

DOI：
10.1007/s00018-021-03978-5
发表时间：
2021-12
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
0
作者：
Umar S;Palasiewicz K;Volin MV;Romay B;Rahat R;Tetali C;Arami S;Guma M;Ascoli C;Sweiss N;Zomorrodi RK;O'Neill LAJ;Shahrara S
通讯作者：
Shahrara S

Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes.

DOI：
10.3389/fimmu.2022.984408
发表时间：
2022
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Torres, Alyssa;Pedersen, Brian;Guma, Monica
通讯作者：
Guma, Monica

Role of mitochondria-bound HK2 in rheumatoid arthritis fibroblast-like synoviocytes.

DOI：
10.3389/fimmu.2023.1103231
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Torres, Alyssa;Kang, Sarah;Mahony, Christopher B.;Cedeno, Martha;Oliveira, Patricia G.;Fernandez-Bustamante, Marta;Kemble, Samuel;Laragione, Teresina;Gulko, Percio S.;Croft, Adam P.;Sanchez-Lopez, Elsa;Miyamoto, Shigeki;Guma, Monica
通讯作者：
Guma, Monica