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Identification of gene biomarkers in patients with postmenopausal osteoporosis.

ABSTRACT: Postmenopausal osteoporosis (PMOP) is a major public health concern worldwide. The present study aimed to provide evidence to assist in the development of specific novel biomarkers for PMOP. Differentially expressed genes (DEGs) were identified between PMOP and normal controls by integrated microarray analyses of the Gene Expression Omnibus (GEO) database, and the optimal diagnostic gene biomarkers for PMOP were identified with LASSO and Boruta algorithms. Classification models, including support vector machine (SVM), decision tree and random forests models, were established to test the diagnostic value of identified gene biomarkers for PMOP. Functional annotations and protein?protein interaction (PPI) network constructions were also conducted. Integrated microarray analyses (GSE56815, GSE13850 and GSE7429) of the GEO database were employed, and 1,320 DEGs were identified between PMOP and normal controls. An 11?gene combination was also identified as an optimal biomarker for PMOP by feature selection and classification methods using SVM, decision tree and random forest models. This combination was comprised of the following genes: Dehydrogenase E1 and transketolase domain containing 1 (DHTKD1), osteoclast stimulating factor 1 (OSTF1), G protein?coupled receptor 116 (GPR116), BCL2 interacting killer, adrenoceptor ?1 (ADRB1), neogenin 1 (NEO1), RB binding protein 4 (RBBP4), GPR87, cylicin 2, EF?hand calcium binding domain 1 and DEAH?box helicase 35. RBBP4 (degree=12) was revealed to be the hub gene of this PMOP?specific PPI network. Among these 11 genes, three genes (OSTF1, ADRB1 and NEO1) were speculated to serve roles in PMOP by regulating the balance between bone formation and bone resorption, while two genes (GPR87 and GPR116) may be involved in PMOP by regulating the nuclear factor??B signaling pathway. Furthermore, DHTKD1 and RBBP4 may be involved in PMOP by regulating mitochondrial dysfunction and interacting with ESR1, respectively. In conclusion, the findings of the current study provided an insight for exploring the mechanism and developing novel biomarkers for PMOP. Further studies are required to test the diagnostic value for PMOP prior to use in a clinical setting.

SUBMITTER: Yang C

PROVIDER: S-EPMC6323213 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Identification of gene biomarkers in patients with postmenopausal osteoporosis.

Yang Chenggang C Ren Jing J Li Bangling B Jin Chuandi C Ma Cui C Cheng Cheng C Sun Yaolan Y Shi Xiaofeng X

Molecular medicine reports 20181212 2

Postmenopausal osteoporosis (PMOP) is a major public health concern worldwide. The present study aimed to provide evidence to assist in the development of specific novel biomarkers for PMOP. Differentially expressed genes (DEGs) were identified between PMOP and normal controls by integrated microarray analyses of the Gene Expression Omnibus (GEO) database, and the optimal diagnostic gene biomarkers for PMOP were identified with LASSO and Boruta algorithms. Classification models, including suppor ...[more]

PMID: 30569177

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Project description:ObjectivePostmenopausal osteoporosis (PMOP) is one of the most commonly occurring conditions worldwide and is characterized by estrogen deficiency as well as persistent calcium loss with age. The aim of our study was to identify significant ferroptosis-associated biomarkers for PMOP.Methods and materialsWe obtained our training dataset from the Gene Expression Omnibus (GEO) database using GSE56815 expression profiling data. Meanwhile, we extracted ferroptosis-associated genes for further analysis. Differentially expressed ferroptosis-associated genes (DEFAGs) between OP patients and normal controls were selected using the "limma" package. We established a ferroptosis-associated gene signature using training models, specifically, random forest (RF) and support vector machine (SVM) models. It was further validated in another dataset (GSE56814) which also showed a high AUC: 0.98, indicating high diagnostic value. Using consensus clustering, the OP patient subtypes were identified. A ferroptosis associated gene (FAG)-Scoring scheme was developed by PCA. The important candidate genes associated with OP were also compared between different ferrclusters and geneclusters.ResultsThere were significant DEFAGs acquired, of which five (HMOX1, HAMP, LPIN1, MAP3K5, FLT3) were selected for establishing a ferroptosis-associated gene signature. Analyzed from the ROC curve, our established RF model had a higher AUC value than the SVM model (RF model AUC:1.00). Considering these results, the established RF model was chosen to be the most appropriate training model. Later, based on the expression levels of the five DEFAGs, a clinical application nomogram was established. The OP patients were divided into two subtypes (ferrcluster A, B and genecluster A, B, respectively) according to the consensus clustering method based on DEFAGs and differentially expressed genes (DEGs). Ferrcluster B and genecluster B had higher ferroptosis score than ferrcluster A and genecluster A, respectively. The expression of COL1A1 gene was significantly higher in ferrcluster B and gencluster B compared with ferrcluster A and gencluster A, respectively, while there is no statistical difference in term of VDR gene, COL1A2 genes, and PTH gene expressions between ferrcluster A and B, together with gencluster A and B.ConclusionsOn the basis of five explanatory variables (HMOX1, HAMP, LPIN1, MAP3K5 and FLT3), we developed a diagnostic ferroptosis-associated gene signature and identified two differently categorized OP subtypes that may potentially be applied for the early diagnosis and individualized treatment of PMOP. The ER gene, VDR gene, IL-6 gene, COL1A1 and COL1A2 genes, and PTH gene are important candidate gene of OP, however, more studies are still anticipated to further elucidate the relationship between these genes and ferroptosis in OP.

Project description:ObjectiveThe literature suggests that not all postmenopausal women suffer from osteoporosis, and the occurrence of postmenopausal osteoporosis is closely related to the genetic susceptibility of genes in the population and the cellular pathways of related genes. To systematically understand the functions of SCIMP gene for osteoporosis, both in vitro and in vivo experiments were analyzed in depth in this integrated study.MethodsThe significantly differentially expressed genes of postmenopausal osteoporosis (PMOP) patients from GEO database were selected. Meanwhile, the primary target gene was also confirmed in clinically recruited individuals using ELISA method; 50 postmenopausal osteoporosis patients with a T-score of -2.5 were randomly enrolled; postmenopausal women with a T-score > -2.5 were included in the non-osteoporotic group (including osteopenia and normal bone mineral density). The associated processes and signaling pathways were deeply investigated with GO and KEGG enrichment analysis. The downstream signaling factors including Erk-1/2, Akt, and IkB-related signaling pathways for the potential gene were evaluated using MG-63 cell line; the MTT, CCK-8, and flow cytometry assays were performed to exam MG-63 cell viability, proliferation, as well as apoptosis, respectively, under different treatments.ResultsBased on the differentially expressed gene analysis for GEO database, PMOP patients displayed 845 differentially expressed genes, including 709 down-regulated and 136 up-regulated ones. Ten genes including SCIMP were significantly differentially expressed (at least three-fold difference). SCIMP was the most markedly decreased in PMOP patients' specimens. Using clinical recruited individuals, the concentration of SCIMP was 96.6 ± 20.8 ng/μL in the PMOP group compared with 168.8 ± 23.5 ng/μL in the control group (p < 0.05). At the same time, the osteoclast differentiation signaling pathway was significantly up-regulated while hedgehogs as well as other signaling pathways were down-regulated based on the KEGG analysis. The phosphorylation level of Akt was markedly blocked in si-SCIMP treatment. Up-regulation of SCIMP increased cell proliferation, inhibited cell apoptosis, and enhanced cell viability in MG-63 cells, which was markedly rescued by AKT phosphorylation inhibitor. Finally, in vivo experiments also confirmed that the upregulation of SCIMP enhanced the structural parameters of rat trabecular bone and the osteogenic activity of bone tissue.ConclusionSCIMP plays a critical role in the pathogenesis of postmenopausal osteoporosis in women. SCIMP influences osteoclasts function through an akt-dependent molecular pathway, and subsequently influences the equilibrium process of bone metabolism. This provides a new insight into the pathogenesis of postmenopausal osteoporosis as well as the clinical treatment of osteoporosis.

Project description:OBJECTIVES:To determine the mechanisms of ubiquitination in postmenopausal osteoporosis and investigate the ubiquitinated spectrum of novel targets between healthy postmenopausal women and postmenopausal osteoporosis patients, we performed ubiquitylome analysis of the whole blood of postmenopausal women and postmenopausal osteoporosis patients. METHODS:To obtain a more comprehensive understanding of the postmenopausal osteoporosis mechanism, we performed a quantitative assessment of the ubiquitylome in whole blood from seven healthy postmenopausal women and seven postmenopausal osteoporosis patients using high-performance liquid chromatography fractionation, affinity enrichment, and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). To examine the ubiquitylome data, we performed enrichment analysis using an ubiquitylated amino acid motif, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS:Altogether, 133 ubiquitinated sites and 102 proteins were quantified. A difference of more than 1.2 times is considered significant upregulation and less than 0.83 significant downregulation; 32 ubiquitinated sites on 25 proteins were upregulated and 101 ubiquitinated sites on 77 proteins were downregulated. These quantified proteins, both with differently ubiquitinated sites, participated in various cellular processes, such as cellular processes, biological regulation processes, response to stimulus processes, single-organism and metabolic processes. Ubiquitin conjugating enzyme activity and ubiquitin-like protein conjugating enzyme activity were the most highly enriched in molecular function of upregulated sites with corresponding proteins, but they were not enriched in downregulated in sites with corresponding proteins. The KEGG pathways analysis of quantified proteins with differentiated ubiquitinated sites found 13 kinds of molecular interactions and functional pathways, such as glyoxylate and decarboxylate metabolism, dopaminergic synapse, ubiquitin-mediated proteolysis, salivary secretion, coagulation and complement cascades, Parkinson's disease, and hippo signaling pathway. In addition, hsa04120 ubiquitin-mediated proteolysis was the most highly enriched in proteins with upregulated sites, hsa04610 complement and coagulation cascades was the most highly enriched in proteins with downregulated ubiquitinated sites, and hsa04114 Oocyte meiosis was the most highly enriched among all differential proteins. CONCLUSION:Our study expands the understanding of the spectrum of novel targets that are differentially ubiquitinated in whole blood from healthy postmenopausal women and postmenopausal osteoporosis patients. The findings will contribute toward our understanding of the underlying proteostasis pathways in postmenopausal osteoporosis and the potential identification of diagnostic biomarkers in whole blood.

Project description:Postmenopausal osteoporosis (PMOP), as well as its associated increased risk for fragility fracture, is one of the most disabling consequences of aging in women. This present study aimed to identify candidate genes that involve pathogenesis of PMOP and the therapeutic mechanism of Liuweidihuang (LWDH) pills on PMOP. We integrated microarray datasets of PMOP derived from the Gene Expression Omnibus (GEO) to screen differentially expressed genes (DEGs) between PMOP and normal controls as well as patients with PMOP and patients after treatment of LWDH pills. GO and KEGG enrichment analysis for DEGs were performed. The shared DEGs, associated with both the pathogenesis of PMOP and the therapeutic mechanism of LWDH, were further analyzed by protein-protein interaction (PPI) network. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the DEGs obtained by our integrated analysis. Compared with normal controls, 1732 DEGs in PMOP were obtained with p<0.05. According to the qRT-PCR results, expression of ATF2, FBXW7, RDX, and RBBP4 was consistent with that in our integrated analysis, generally. GO and KEGG enrichment analysis showed that those DEGs were significantly enriched in regulation of transcription, DNA-dependent, cytoplasm, protein binding, and MAPK signaling pathway. A total of 58 shared DEGs in PMOP versus normal control and in patients with PMOP versus patients after LWDH treatment were identified, which had opposite expression trend in these two comparisons. In the PPI network, CSNK2A1, ATF2, and FBXW7 were three hub proteins. Three genes including ATF2, FBXW7, and RDX were speculated to be therapeutic targets of LWDH for PMOP based on BATMAN-TCM database. We speculated that three genes of ATF2, FBXW7, and RDX may play crucial roles in both pathogenesis of PMOP and therapeutic mechanism of LWDH on PMOP. Our results may provide clues for the molecular pathogenesis of PMOP and offer new possibilities for treatment of PMOP.

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Identification of gene biomarkers in patients with postmenopausal osteoporosis.

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Identification of gene biomarkers in patients with postmenopausal osteoporosis.

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