Identification and analysis of mitochondria-related central genes in steroid-induced osteonecrosis of the femoral head, along with drug prediction.
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ABSTRACT:
SUBMITTER: Ma Z
PROVIDER: S-EPMC10879930 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
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Identification and analysis of mitochondria-related central genes in steroid-induced osteonecrosis of the femoral head, along with drug prediction.
Ma Zheru Z Sun Jing J Jiang Qi Q Zhao Yao Y Jiang Haozhuo H Sun Peng P Feng Wei W
Frontiers in endocrinology 20240207
<h4>Purpose</h4>Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory orthopedic hip joint disease that primarily affects middle-aged and young individuals. SONFH may be caused by ischemia and hypoxia of the femoral head, where mitochondria play a crucial role in oxidative reactions. Currently, there is limited literature on whether mitochondria are involved in the progression of SONFH. Here, we aim to identify and validate key potential mitochondrial-related genes in SONFH t ...[more]
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Project description:ObjectiveThis study aimed to identify and evaluate genes associated with cellular autophagy in steroid hormonal femoral head necrosis.MethodsAutophagy-related differentially expressed genes (ARDEGs) in steroid-induced osteonecrosis of the femoral head (SONFH) were identified by obtaining the intersection of differentially expressed genes (DEGs) and autophagy-related genes in a SONFH Gene Expression Omnibus dataset. The ARDEGs were screened, and correlations between gene expression and immune cell infiltration were evaluated. Finally, the validation of hub genes was undertaken through quantitative real-time-PCR.ResultsA comparison of peripheral blood samples from patients with and without SONFH revealed 189 DEGs. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses showed that the DEGs were related to various biologic processes (e.g., neutrophil activation) and pathways (e.g., hematopoietic cell lineage). The expression levels of these genes were correlated with the infiltration of multiple immune cell types. Among the 189 putative autophagy-related genes associated with SONFH, three genes, RPL6, RPL9, and RPL23, were identified as candidate biomarkers or therapeutic targets based on network analysis and their correlations with immune cell subtypes. The quantitative real-time polymerase chain reaction results confirmed our prediction regarding the mRNA expression of RPL9 and RPS6.ConclusionIn this study, we identified 189 putative autophagy-related genes associated with SONFH, and the prediction of down-regulated genes RPL9 and RPS6 was validated using PCR, thereby expanding our understanding of the contribution of autophagy to SONFH.
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Project description:Steroid-induced osteonecrosis of the femoral head (ONFH) is a common orthopaedic disease of which early detection remains clinically challenging. Accumulating evidences indicated that circulating microRNAs (miRNAs) plays vital roles in the development of several bone diseases. However, the association between circulating miRNAs and steroid-induced ONFH remains elusive. miRNA microarray was performed to identify the differentially abundant miRNAs in the serums of systemic lupus erythematosus (SLE) patients with steroid-induced ONFH as compared with SLE control and healthy control group. We predicted the potential functions of these differentially abundant miRNAs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and reconstructed the regulatory networks of miRNA-mRNA interactions. Our data indicated that there were 11 differentially abundant miRNAs (2 upregulated and 9 downregulated) between SLE-ONFH group and healthy control group and 42 differentially abundant miRNAs (14 upregulated and 28 downregulated) between SLE-ONFH group and SLE control group. We also predicted the potential functions of these differentially abundant miRNAs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and reconstructed the regulatory networks of miRNA-mRNA interactions. These findings corroborated the idea that circulating miRNAs play significant roles in the development of ONFH and may serve as diagnostic markers and therapeutic targets.
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Project description:BackgroundSteroid-induced osteonecrosis of the femoral head (ONFH) is a common hip joint disease and is difficult to be diagnosed early. At present, the pathogenesis of steroid-induced ONFH remains unclear, and recognized and effective diagnostic biomarkers are deficient. The present study aimed to identify potentially important genes and signaling pathways involved in steroid-induced ONFH and investigate their molecular mechanisms.MethodsMicroarray data sets GSE123568 (peripheral blood) and GSE74089 (cartilage) were obtained from the Gene Expression Omnibus database, including 34 ONFH samples and 14 control samples. Morpheus software and Venn diagram were used to identify DEGs and co-expressed DEGs, respectively. Besides, we conducted Kyoto Encyclopedia of Genome (KEGG) and gene ontology (GO) pathway enrichment analysis. We construct a protein-protein interaction (PPI) network through GEO2R and used cytoHubba to divide the PPI network into multiple sub-networks. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the bioinformatics analysis results.ResultsA total of 118 intersecting DEGs were obtained between the peripheral blood and cartilage samples, including 40 upregulated genes and 78 downregulated genes. Then, GO and KEGG pathway enrichment analysis revealed that upregulated DEGs focused on the signaling pathways related to staphylococcus aureus infection, leishmaniasis, antigen processing, and presentation, as well as asthma and graft-versus-host disease. Downregulated genes were concentrated in the FoxO signaling pathway, AMPK signaling pathway, signaling pathway regulating stem cell pluripotency, and mTOR signaling pathway. Some hub genes with high interactions such as CXCR1, FPR1, MAPK1, FOXO3, FPR2, CXCR2, and TYROBP were identified in the PPI network. The results of qRT-PCR demonstrated that CXCR1, FPR1, and TYROBP were upregulated while MAPK1 was downregulated in peripheral blood of steroid-induced ONFH patients. This was consistent with the bioinformatics analysis.ConclusionsThe present study would provide novel insight into the genes and associated pathways involved in steroid-induced ONFH. CXCR1, FPR1, TYROBP, and MAPK1 may be used as potential drug targets and biomarkers for the diagnosis and prognosis of steroid-induced ONFH.
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Project description:Angiogenesis is an important event in steroid-associated osteonecrosis of the femoral head (SONFH). Here we performed miRNA microarray with SONFH tissues (ONs) and the adjacent normal tissues (NLs) to select the angiogenic miRNA. The results showed that miR-210 was differentially expressed in SONFH versus normal tissues. Unexpectedly, its specific transcription factor, hypoxia-inducible factor-1α, was shown of no significant changes in ONs compared with NLs. Further Bisulfite sequencing revealed that miR-210 is embedded in a CpG island and miR-210 gene has 2 CpG sites with lower methylation percentage in ONs compared with NLs. Additionally, ONs with lower miR-210 gene methylation exhibited higher miR-210 expression. Next, we found that the endothelial cells treated with demethylating agents could significantly increase the expression of miR-210, along with promoted cell viability and differentiation. Some angiogenic genes (VEGF, bFGF, TNF-α and PCNA) were up-regulated as well. In addition, the supernatant of the cells after demethylation treatment displayed an enhanced ability of recruiting new microvessels in vivo. Taken together, our study not only provides novel insights into the regulation of angiogenesis in this disease, but also reveals a therapeutic opportunity for treatment of SONFH patients with demethylating agents.
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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.
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Project description:The leading cause of steroid-induced femoral head osteonecrosis (ONFH) is the imbalance of bone homeostasis. Bone marrow-derived mesenchymal stem cell (BMSC) differentiation and fate are closely associated with bone homeostasis imbalance. Blocking monoacylglycerol lipase (MAGL) could effectively ameliorate ONFH by mitigating oxidative stress and apoptosis in BMSCs induced by glucocorticoids (GC). Nevertheless, whether MAGL inhibition can modulate the balance during BMSC differentiation, and therefore improve ONFH, remains elusive. Our study indicates that MAGL inhibition can effectively rescue the enhanced BMSC adipogenic differentiation caused by GC and promote their differentiation toward osteogenic lineages. Cannabinoid receptor 2 (CB2) is the direct downstream target of MAGL in BMSCs, rather than cannabinoid receptor 1(CB1). Using RNA sequencing analyses and a series of in vitro experiments, we confirm that the MAGL blockade-induced enhancement of BMSC osteogenic differentiation is primarily mediated by the phosphoinositide 3-kinases (PI3K)/ the serine/threonine kinase (AKT)/ (glycogen synthase kinase-3 beta) GSK3β pathway. Additionally, MAGL blockade can also reduce GC-induced bone resorption by directly suppressing osteoclastogenesis and indirectly reducing the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in BMSCs. Thus, our study proposes that the therapeutic effect of MAGL blockade on ONFH is partly mediated by restoring the balance of bone homeostasis and MAGL may be an effective therapeutic target for ONFH.
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Project description:Early diagnosis is crucial to increase the chances of conservation treatment for patients with steroid-induced osteonecrosis of the femoral head (SIONFH). This study aimed to identify serum peptides as potential biomarkers to diagnose SIONFH.
2020-06-16 | PXD019805 |