Distinct inflammatory gene expression in extraocular muscle and fat from patients with Graves’ orbitopathy

Romero-Kusabara, Ivana Lopes; Filho, José Vital; Scalissi, Nilza Maria; Melo, Keli Cardoso de; Demartino, Giovanni; Longui, Carlos Alberto; Melo, Murilo Rezende; Cury, Adriano Namo

doi:10.1530/eje-16-0945

Cited by 16 publications

(10 citation statements)

References 44 publications

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“…While our data revealed several differentially expressed gene profiles between diseased and control patients, we found that genes related to developmental morphogenesis and lineage commitment were predominantly dysregulated in TAO. Unlike previous gene expression profiling studies that analyzed orbital fat pads and extraocular muscle, 17 , 38 , 44 the current study did not detect any significant different expression in genes related to inflammation (RNAseq dataset, Table 2 ). These findings suggest that our data may reveal the intrinsic cellular characteristics of the stem cell niche that are otherwise masked by the massive immunogenic response in the tissue from TAO patients.…”

Section: Discussioncontrasting

confidence: 93%

RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy

Tao

Ayala-Haedo

Field

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeThe purpose of this study was to characterize the intrinsic cellular properties of orbital adipose-derived stem cells (OASC) from patients with thyroid-associated orbitopathy (TAO) and healthy controls.MethodsOrbital adipose tissue was collected from a total of nine patients: four controls and five patients with TAO. Isolated OASC were characterized with mesenchymal stem cell–specific markers. Orbital adipose-derived stem cells were differentiated into three lineages: chondrocytes, osteocytes, and adipocytes. Reverse transcription PCR of genes involved in the adipogenesis, chondrogenesis, and osteogenesis pathways were selected to assay the differentiation capacities. RNA sequencing analysis (RNA-seq) was performed and results were compared to assess for differences in gene expression between TAO and controls. Selected top-ranked results were confirmed by RT-PCR.ResultsOrbital adipose-derived stem cells isolated from orbital fat expressed high levels of mesenchymal stem cell markers, but low levels of the pluripotent stem cell markers. Orbital adipose-derived stem cells isolated from TAO patients exhibited an increase in adipogenesis, and a decrease in chondrogenesis and osteogenesis. RNA-seq disclosed 54 differentially expressed genes. In TAO OASC, expression of early neural crest progenitor marker (WNT signaling, ZIC genes and MSX2) was lost. Meanwhile, ectopic expression of HOXB2 and HOXB3 was found in the OASC from TAO.ConclusionOur results suggest that there are intrinsic genetic and cellular differences in the OASC populations derived from TAO patients. The upregulation in adipogenesis in OASC of TAO may be is consistent with the clinical phenotype. Downregulation of early neural crest markers and ectopic expression of HOXB2 and HOXB3 in TAO OASC demonstrate dysregulation of developmental and tissue patterning pathways.

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Section: Discussioncontrasting

confidence: 93%

RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy

Tao

Ayala-Haedo

Field

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…As Table 3 shows, the expression of IL-1, IL-6, IL-8, IL-10, IL-17, IFN-γ, and TNF-α was significantly upregulated in EOMs from GO patients. Cytokines such as IL-6, IFN-γ and TNF-α were previously reported to promote fibroblast proliferation and differentiation in GO [17]. More importantly, we found by KEGG analysis of the biological pathways that 12 of 19 pathways were involved in immune and inflammatory responses.…”

Section: Discussionmentioning

confidence: 55%

“…Inflammation in the orbit of patients with GO is accepted to be caused by autoimmune responses and inflammatory cytokine release [17,18]. RNA methylation has been reported to regulate T-cell homeostasis and the inflammatory response by targeting inflammatory pathways [19].…”

Section: Discussionmentioning

confidence: 99%

“…(2) Our specimens were collected from the thickest area of the EOM consistently and they accurately represent the pathologic status of the GO. However, in many previous publications, the area of the specimens obtained for the study of the ECM expression have not been defined [17,24,28]. Since gene expression may be variable in the tendon and the muscle component of GO specimens [29], this factor may influence the expression of the ECM gene.…”

Section: Discussionmentioning

confidence: 99%

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The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy

Zhu

et al. 2020

Eye and Vis

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Purpose To investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO). Methods Surgically excised extraocular muscles from 7 patients with GO and 5 subjects without GO were used. The global m6A levels in the specimens were determined using an m6A RNA methylation quantification kit. RNA sequencing (RNA-seq) was used to analyze the molecules involved in the regulation of m6A RNA methylation and the differential expression of mRNAs between the two groups (4 eyes, respectively). The expression of m6A RNA modification genes was evaluated by real-time PCR. The functional implications of the gene alterations between the GO and control specimens were determined by Gene Ontology analysis. Results The m6A level was significantly increased in the specimens of GO patients compared to the control specimens (P < 0.05). The expression of m6A methylation regulators, such as WT1 associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), E74 like ETS transcription factor 3 (ELF3), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), YTHDF3 and YTH domain containing 2 (YTHDC2), was significantly upregulated (P < 0.05). Gene Ontology enrichment analysis showed that the most highly upregulated genes and biological pathways were related to the immune response and inflammatory processes such as lymphocyte activation, leukocyte differentiation, cytokine production and cytokine-mediated signaling pathways. Conclusions Our results suggest that m6A methylation may play a critical role in the pathogenesis of GO and that targeting genes that regulate m6A methylation may provide a new therapeutic approach for GO.

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“…Ряд а второв пола га ют, что истинная рефрактерность -геномная. То есть одной из основных причин снижения чувствительности к ГК, отсутствия эффекта от их применения является генетическая вариабельность, в том числе полиморфизм на уровне глюкокортикоидного рецептора (ГКР) NR3C1 [9,10]. Целью настоящего исследования стало выявление у больных ЭОП взаимосвязи между полиморфизмом гена ГКР NR3C1 и ответом на терапию ГК.…”

Section: эффективная фармакотерапия 33/2019unclassified

Genetic Factors of Glucocorticoid Resistance in Patients with Grave`s Ophthalmopathy

Saakyan¹,

Panteleyeva²,

Батырбекова³

et al. 2019

EPh

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Distinct inflammatory gene expression in extraocular muscle and fat from patients with Graves’ orbitopathy

Cited by 16 publications

References 44 publications

RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy

RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy

The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy

Genetic Factors of Glucocorticoid Resistance in Patients with Grave`s Ophthalmopathy

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