Dataset Information

Combined effect of tnf-? polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head.

ABSTRACT: Tumor necrosis factor (TNF)-? is a proinflammatory cytokine, some studies reported that TNF-? gene plays important role in the pathogenesis of SONFH. And the polymorphisms of TNF-? were presented as risk factors for steroid-induced osteonecrosis of the femoral head (SONFH). Meanwhile, various environment factors involve in the pathogenesis of SONFH. Our study aimed to investigate the interaction effect of TNF-? polymorphisms and hypoxia factor on SONFH.120 patients with SONFH and 100 healthy people, matched with the cases on age and sex, participated in this study. DNA was extracted from all participants. According to previous studies, genotyping of TNF-? polymorphisms (rs1800629, rs1799964 and rs1800630) was tested with the method of PCR-RDB (Reverse Dot Blot). Environmental factors were also chose. Logistic regression analysis was used to analyze the interaction between TNF-? polymorphisms and environment factors on SONFH.The polymorphisms of rs1800629 and rs1800630 were significantly associated with SONFH (OR: 3.70, 9.93). Patients with hypoxia history were found higher (65.00%) compared with the healthy controls (43.00%). For the person with hypoxic history, GG and AG+AA genotypes of rs1800629 could increase their risk to suffer SONFH (OR: 2.12, 3.78). If the patients with the variant genotypes of rs1800630 experienced hypoxia state, then the risk for SONFH increased 2.41 folds.We concluded that the onset of SONFH was influenced by TNF-? and hypoxia history. There existed strong interaction between TNF-? and hypoxia history.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4440152 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Combined effect of tnf-α polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head.

Liu Yaosheng Y Jiang Weihao W Liu Shubin S Su Xiuyun X Zhou Shiguo S

International journal of clinical and experimental pathology 20150301 3

<h4>Objective</h4>Tumor necrosis factor (TNF)-α is a proinflammatory cytokine, some studies reported that TNF-α gene plays important role in the pathogenesis of SONFH. And the polymorphisms of TNF-α were presented as risk factors for steroid-induced osteonecrosis of the femoral head (SONFH). Meanwhile, various environment factors involve in the pathogenesis of SONFH. Our study aimed to investigate the interaction effect of TNF-α polymorphisms and hypoxia factor on SONFH.<h4>Methods</h4>120 patie ...[more]

PMID: 26045843

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Project description:BackgroundThe etiology and pathology osteonecrosis of the femoral head (ONFH) are not completely clarified. As a cytokine participating in systemic inflammation, tumor necrosis factor alpha (TNFα) has been shown to be involved in the pathogenesis of ONFH. However, the role of TNFα in ONFH is not clearly clarified. In the present study, we investigated the effects of TNFα on proliferation, angiogenesis, and osteogenic differentiation of rat bone mesenchymal stem cells (rMSCs) and the underlying mechanisms.MethodsAll femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we evaluated TNFα content by ELISA and the relative expression levels of genes by quantitative real-time PCR and western blot. Also, immunohistochemistry staining was performed to observe the expression of Runx2 in the bone samples. Chick embryo chorioallantoic membrane (CAM) assay was performed to observe the effect of TNFα on angiogenesis. The genomic DNAs were treated by bisulfite modification, and methylation status of CpG sites in the CpG islands of human and rat Runx2 gene promoter was determined by DNA sequencing. The binding of H3K4me3 and H3K27me3 in Runx2 promoter was checked by ChIP assay. RNA-seq analysis was used to find out the genes and pathways changed by TNFα in rMSCs.ResultsThe results demonstrate TNFα promotes cell proliferation and angiogenesis whereas inhibits osteogenesis. Epigenetic regulations including DNA methylation and histone modifications play important roles in mediating the effect of TNFα on osteogenic differentiation. We find an increased rate of CpG methylation in rat Runx2 promoter in TNFα-treated rMSCs, as well as significantly increased occupancy of H3K27me3 in Runx2 gene promoter. The content of TNFα in necrotic tissue is much lower than that of normal tissue. And relevantly, human Runx2 promoter is demethylated in necrotic tissue using bone samples from patient with ONFH. In addition, we have observed that Wnt signaling pathway is inhibited by TNFα as multiple Wnts are markedly decreased in TNFα-treated rMSCs by RNA-seq analysis.ConclusionTaken together, our study shows that TNFα plays complicated roles in the pathogenesis of ONFH, including proliferation, angiogenesis, and osteogenesis. Targeting TNFα should not be considered as an applicable strategy to inhibit the progression of ONFH.

Project description:PurposeSteroid-induced necrosis of the femoral head (SONFH) is a refractory orthopedic hip disease occurring in young and middle-aged people, with glucocorticoids being the most common cause. Previous experimental studies have shown that cell pyroptosis may be involved in the pathological process of SONFH, but its pathogenesis in SONFH is still unclear. This study aims to screen and validate potential pyroptosis-related genes in SONFH diagnosis by bioinformatics analysis to further elucidate the mechanism of pyroptosis in SONFH.MethodsThere were 33 pyroptosis-related genes obtained from the prior reviews. The mRNA expression was downloaded from GSE123568 dataset in the Gene Expression Omnibus (GEO) database, including 10 non-SONFH (following steroid administration) samples and 30 SONFH samples. The pyroptosis-related differentially expressed genes involved in SONFH were identified with "affy" and "limma" R package by intersecting the GSE123568 dataset with pyroptosis genes. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the pyroptosis-related differentially expressed genes involved in SONFH were conducted by "clusterProfiler" R package and visualized by "GOplot" R package. Then, the correlations between the expression levels of the pyroptosis-related differentially expressed genes involved in SONFH were confirmed with "corrplot" R package. Moreover, the protein-protein interaction (PPI) network was analysed by using GeneMANIA database. Next, The ROC curve of pyroptosis-related differentially expressed genes were analyzed by "pROC" R package.ResultsA total of 10 pyroptosis-related differentially expressed genes were identified between the peripheral blood samples of SONFH patients and non-SONFH patients based on the defined criteria, including 20 upregulated genes and 10 downregulated genes. The GO and KEGG pathway enrichment analyses revealed that these 10 pyroptosis-related differentially expressed genes involved in SONFH were particularly enriched in cysteine-type endopeptidase activity involved in apoptotic process, positive regulation of interleukin-1 beta secretion and NOD-like receptor signaling pathway. Correlation analysis revealed significant correlations among the 10 differentially expressed pyroptosis-related genes involved in SONFH. The PPI results demonstrated that the 10 pyroptosis-related differentially expressed genes interacted with each other. Compared to non-SONFH samples, these pyroptosis-related differentially expressed genes had good predictive diagnostic efficacy (AUC = 1.000, CI = 1.000-1.000) in the SONFH samples, and NLRP1 had the highest diagnostic value (AUC: 0.953) in the SONFH samples.ConclusionsThere were 10 potential pyroptosis-related differentially expressed genes involved in SONFH were identified via bioinformatics analysis, which might serve as potential diagnostic biomarkers because they regulated pyroptosis. These results expand the understanding of SONFH associated with pyroptosis and provide new insights to further explore the mechanism of action and diagnosis of pyroptosis associated in SONFH.

Dataset Information

Combined effect of tnf-? polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head.

Publications

Combined effect of tnf-α polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head.

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