IL-21 promotes osteoblastic differentiation of human valvular interstitial cells through the JAK3/STAT3 pathway

Liu, Zongtao; Wang, Yixuan; Shi, Jing; Chen, Si; Xu, Long; Li, Fēi; Dong, Nianguo

doi:10.7150/ijms.49533

Cited by 15 publications

(12 citation statements)

References 30 publications

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“…STAT3 is a JAK3-related TF. Knocking down STAT3 in valvular interstitial cells inhibited expression of the osteoblastic markers, alkaline phosphatase (ALP) and RUNX family transcription factor 2 (RUNX2), and decreased matrix calcium deposition after pro-calcific stimulation ( 71 ). Moreover, p-STAT3 was also upregulated in calcified aortic valves and has clinical potential to inhibit the progression of valve calcification in an inflammatory milieu ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease

Guo

Zhang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCalcific aortic valve disease (CAVD) is one of the most frequently occurring valvular heart diseases among the aging population. Currently, there is no known pharmacological treatment available to delay or reverse CAVD progression. The regulation of gene expression could contribute to the initiation, progression, and treatment of CAVD. Non-coding RNAs (ncRNAs) and transcription factors play essential regulatory roles in gene expression in CAVD; thus, further research is urgently needed.Materials and MethodsThe gene-expression profiles of GSE51472 and GSE12644 were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified in each dataset. A protein-protein-interaction (PPI) network of DEGs was then constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and functional modules were analyzed with ClusterOne plugin in Cytoscape. Furthermore, Gene Ontology-functional annotation and Kyoto Encyclopedia of Genes and Genomes-pathway analysis were conducted for each functional module. Most crucially, ncRNAs and transcription factors acting on each functional module were separately identified using the RNAInter and TRRUST databases. The expression of predicted transcription factors and key genes was validated using GSE51472 and GSE12644. Furthermore, quantitative real-time PCR (qRT-PCR) experiments were performed to validate the differential expression of most promising candidates in human CAVD and control samples.ResultsAmong 552 DEGs, 383 were upregulated and 169 were downregulated. In the PPI network, 15 functional modules involving 182 genes and proteins were identified. After hypergeometric testing, 45 ncRNAs and 33 transcription factors were obtained. Among the predicted transcription factors, CIITA, HIF1A, JUN, POU2F2, and STAT6 were differentially expressed in both the training and validation sets. In addition, we found that key genes, namely, CD2, CD86, CXCL8, FCGR3B, GZMB, ITGB2, LY86, MMP9, PPBP, and TYROBP were also differentially expressed in both the training and validation sets. Among the most promising candidates, differential expressions of ETS1, JUN, NFKB1, RELA, SP1, STAT1, ANCR, and LOC101927497 were identified via qRT-PCR experiments.ConclusionIn this study, we identified functional modules with ncRNAs and transcription factors involved in CAVD pathogenesis. The current results suggest candidate molecules for further research on CAVD.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease

Guo

Zhang

et al. 2022

Front. Cardiovasc. Med.

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“…Previous studies have shown increased IL-6, IL-21, IL-27, and IL-33 in PAP lesions [28-30], which is in accordance with the results presented here. These cytokines have also been shown to have osteogenic activity [31][32][33][34]. Among the seven cytokines that we found reduced in PAP lesions, IL-9, IL-23, and TNFα have previously been found to be increased in PAP lesions [28].…”

Section: Discussionmentioning

confidence: 59%

Disease-related cytokine markers in persistent apical periodontitis – associated with comorbidities?

Agger

Reseland

Hjelkrem

et al. 2022

Preprint

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Objectives: This study aimed to identify disease-related markers in persistent apical periodontitis (PAP) biopsies and examine whether these were associated with comorbidities. Materials and method: The levels of the cytokines GM-CSF, IFN-γ, IL-2, IL-6, IL-9, IL-10, IL-13, IL-15, IL-17E/IL-25, IL-21, IL-23, IL-27, IL-28A/IFN -λ2, IL-33, MIP-3α/CCL20 and TNF-α were determined in lesions from patients with persistent apical periodontitis (n = 20) and compared to healthy bone samples (n = 20). Results: We identified eleven cytokines to be differently expressed, and among them, IL-2, IL-6, IL-17E, IL-21, and IL-27 appeared to drive the discrepancy between the disease and healthy groups. The levels of T follicular helper (Tfh) cell promoting cytokines (IL-21, IL-6, IL-27) were enhanced while T helper (Th) 1 cell promoting cytokine (IL-2), Th2 cell promoting cytokine (IL-13), and Th17 cell promoting cytokine (IL-17E) were reduced in the PAP group. The data also indicate that Tfh cell differentiation (IL-21), along with Th1 (GM-CSF, IFNγ), Th2 (IL-13), and Th17 (GM-CSF) cell differentiation, might be increased in the subpopulation of patients suffering from rheumatoid arthritis, whereas no differences were found in patients with cardiovascular diseases. Conclusions: A cluster of potential cellular markers for PAP was identified. The lesions contained additional factors that might be associated with differentiation of various T cell populations. Clinical Relevance: Molecular analyses of PAP may result in identification of prognostic markers.

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“…We quantified the mRNA expression of STAT3 throughout adipogenesis, and we verified that its expression increases significantly after three days of induction and maintains this pattern until day 14 ( Figure 4(b) ). Liu et al (2020) have demonstrated that IL21 can promote osteogenic differentiation by activating JAK3/STAT3 pathway in human valvular interstitial cells [ 35 ]. Therefore, we questioned whether IL21R had any role in the differentiation process.…”

Section: Resultsmentioning

confidence: 99%

Interleukin 21 Receptor Affects Adipogenesis of Human Adipose-Derived Stem/Stromal Cells

Falavinha

Barisón

Rebelatto

et al. 2022

Stem Cells International

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Dysfunctions in adipose tissue cells are responsible for several obesity-related metabolic diseases. Understanding the process of adipocyte formation is thus fundamental for understanding these diseases. The adipocyte differentiation of adipose-derived stem/stromal cells (ADSCs) showed a reduction in the mRNA level of the interleukin 21 receptor (IL21R) during this process. Although the receptor has been associated with metabolic diseases, few studies have examined its function in stem cells. In this study, we used confocal immunofluorescence assays to determine that IL21R colocalizes with mitochondrial protein ATP5B, ALDH4A1, and the nucleus of human ADSCs. We demonstrated that silencing and overexpression of IL21R did not affect the cell proliferation and mitochondrial activity of ADSCs. However, IL21R silencing did reduce ADSC adipogenic capacity. Further studies are needed to understand the mechanism involved between IL21R and the adipogenic differentiation process.

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IL-21 promotes osteoblastic differentiation of human valvular interstitial cells through the JAK3/STAT3 pathway

Cited by 15 publications

References 30 publications

Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease

Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease

Disease-related cytokine markers in persistent apical periodontitis – associated with comorbidities?

Interleukin 21 Receptor Affects Adipogenesis of Human Adipose-Derived Stem/Stromal Cells

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