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:
- 金额:$ 33.71万
- 依托单位:
- 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:
- 关键词:AddressAdultAffectApoptosisArthritisBindingCartilageCellsCellular Metabolic ProcessColorCombined Modality TherapyConfocal MicroscopyCytosolDataDevelopmentDiseaseEndoplasmic ReticulumEnzymesFibroblastsGlucose TransporterGlycolysisGlycolysis InhibitionGrowthHexokinase 2HomeostasisHypoxiaImmunosuppressionImpairmentIn VitroInflammationInflammatoryInflammatory ArthritisInjectionsInterleukin-6Intra-Articular InjectionsJointsKneeLesionMacrophage ActivationMembraneMembrane ProteinsMetabolicMetabolismMiconazoleMitochondriaMolecularMusNormal CellPathogenesisPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhenotypePhosphorylationPhosphotransferasesPlayPopulationProcessProtein IsoformsRheumatismRheumatoid ArthritisRiskRoleSamplingSeveritiesSignal PathwayStromal CellsSynovial CellSynovial FluidSynovial MembraneSynovitisTestingTherapeuticThickTissuesUp-RegulationVoltage-Dependent Anion ChannelWorkadenoviral-mediatedarthropathiesbonebone cellcell motilitycell typeextracellularglucose metabolismhexokinaseimprovedin vivoinsightjoint destructionjoint inflammationknock-downmacrophagemigrationmutantnovelnovel therapeuticsoverexpressionpeptide drugpublic health relevancevoltage-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
在风湿性关节炎中靶向己糖激酶2(变化以下划线表示)
己糖激酶(HKS)催化葡萄糖代谢的第一个关键步骤。HK 2是主要的
可诱导的同种型,并且在正常成人组织中具有有限的表达分布。细胞群,
增加的糖酵解和HK 2表达具有强大的生长优势。HK 2本地化也在
线粒体,并且其相互作用增加葡萄糖代谢并保护线粒体免于凋亡。
因此,线粒体HK 2易位促进几种细胞类型中的活化表型。
成纤维细胞样滑膜细胞(FLS)和巨噬细胞(MO)是类风湿关节炎(RA)的重要组成部分
炎症的滑膜,并有助于破坏性关节炎症的启动和持续。FLS从
RA患者表现出独特的攻击性特征,这些特征是自主的和垂直传播的。MO等
在RA的发病机制中也至关重要。滑膜下层MO数量的增加是早期的
作为活动性风湿病的标志,高数量的MO是炎性关节炎的突出特征。
病变值得注意的是,葡萄糖代谢在活化的FLS和MO中的关键作用已经被强调,
我们最近的工作
我们的初步数据表明,虽然HK 1在OA和RA滑膜中表达,但HK 2在RA滑膜中表达。
表达与MO和FLS标记物共定位,并且仅在RA中观察到,而在OA滑膜中未观察到。
样品我们还表明,HK 2调节关键FLS功能,因为HK 2敲低损害FLS侵袭。
相反,HK 2过表达增加FLS侵袭和迁移率。值得注意的是,乳酸盐和PLOD 2,
其参与细胞迁移和侵袭,在HK 2表达后上调。上调
细胞外乳酸盐也表明代谢向加速糖酵解代谢转变。HK 2突变体
缺乏其细胞结合基序(HK 2 ΔN)逆转了侵袭表型。在MO中,
使HK 2与线粒体分离,损害IL-6分泌。重要的是,腺病毒介导的
通过关节内注射在膝关节中的HK 2诱导滑膜厚度,当
关节内注射HK 2 ΔN。最后,HK 2F/F-Col 1a 1小鼠,其在FLS中缺失HK 2以及其他非-
用克霉唑处理,使HK 2从线粒体上解离,
降低关节炎的严重程度。因此,我们将检验线粒体HK 2是FLS的关键调节子的假设
表型和MO激活,这有助于RA中的关节破坏。HK 2的鉴定,
在RA滑膜组织中升高细胞葡萄糖代谢的亚型特异性贡献者提供了一种更安全的
方法比全球糖酵解抑制。HK 2可以选择性地作为目标,而不会损害
在正常细胞中的系统稳态或相应的代谢功能作为新的附加的
独立于全身免疫抑制的RA关节疾病联合治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Monica Guma其他文献
Monica Guma的其他文献
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{{ truncateString('Monica Guma', 18)}}的其他基金
Can circulating bile acids predict knee OA progression?
循环胆汁酸可以预测膝关节 OA 的进展吗?
- 批准号:
10575385 - 财政年份:2023
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
10161179 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
9896651 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
9764274 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
10633710 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
10606368 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
10410487 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Targeting hexokinase-2 in rheumatoid arthritis
靶向己糖激酶 2 治疗类风湿性关节炎
- 批准号:
10405768 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Choline metabolites as biomarkers in rheumatoid arthritis
胆碱代谢物作为类风湿性关节炎的生物标志物
- 批准号:
8895115 - 财政年份:2015
- 资助金额:
$ 33.71万 - 项目类别:
Choline metabolites as biomarkers in rheumatoid arthritis
胆碱代谢物作为类风湿性关节炎的生物标志物
- 批准号:
9022409 - 财政年份:2015
- 资助金额:
$ 33.71万 - 项目类别:
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