Dataset Information

Bioinformatics Analysis Reveals the Altered Gene Expression of Patients with Postmenopausal Osteoporosis Using Liuweidihuang Pills Treatment.

ABSTRACT: 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.

SUBMITTER: Gong R

PROVIDER: S-EPMC6369488 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Bioinformatics Analysis Reveals the Altered Gene Expression of Patients with Postmenopausal Osteoporosis Using Liuweidihuang Pills Treatment.

Gong Rui R Ren Shan S Chen Menghui M Wang Yanli Y Zhang Guoliang G Shi Lijuan L Zhang Cuizhao C Su Ruihong R Li Yukun Y

BioMed research international 20190127

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 p ...[more]

PMID: 30809532

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Project description:BackgroundPostmenopausal osteoporosis, a common yet chronic systemic metabolic disease, has become a major public health problem due to life expectancy increasing around the world. The differentiation of mesenchymal stem cells (MSCs) into osteoblasts, and the differentiation of circulating monocyte cells into osteoclasts, play an important role in the balance of bone metabolism. However, when both undergo pathological changes, it can lead to abnormalities, resulting in osteoporosis. This study aims to explore a new biomarker for postmenopausal osteoporosis, thereby providing a new entry point for bioinformatic research into the clinical diagnosis and treatment of the disease.MethodsUsing the Gene Expression Omnibus (GEO) database, microarray analysis was conducted to identify differentially expressed genes in MSCs and monocytes in both postmenopausal osteoporosis patients and a healthy control group. The Database for Annotation, Visualization and Integrated Discovery (DAVID) database was used to analyze the function and enrichment of the selected genes, and a protein-protein interaction (PPI) network was constructed from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website and displayed in Cytoscape. To achieve the final results, module analysis of the PPI network was performed by using Molecular Complex Detection (MCODE).ResultsWe identified 45 high-expression and 26 low-expression genes through the study, all of which underwent pathway enrichment analysis. This enrichment was observed in the cell cycle regulation, osteoclast differentiation, tumor necrosis factor (TNF) signaling pathway, and RNA transport. The top 10 hub genes of the PPI network were SF3B1, SRSF5, FUBP1, SRSF3, TIA1, KHSRP, LUC7L3, PNN, SRC, and ATRX. Comparing the MSCs and monocytes between the postmenopausal osteoporosis patients and the healthy control group, we noted that the expression of the above genes differed greatly.ConclusionsThrough bioinformatic analysis and clinical specimen validation, our study provides a new way for exploring the pathogenesis of postmenopausal osteoporosis. Most importantly, it suggests that the hub genes, SF3B1, SRSF5, FUBP1, KHSRP, and SRC, may become new diagnostic markers and therapeutic targets for diagnosing and treating postmenopausal osteoporosis in the future.

Project description: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 β1 (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‑κB 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.

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.

Dataset Information

Bioinformatics Analysis Reveals the Altered Gene Expression of Patients with Postmenopausal Osteoporosis Using Liuweidihuang Pills Treatment.

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Bioinformatics Analysis Reveals the Altered Gene Expression of Patients with Postmenopausal Osteoporosis Using Liuweidihuang Pills Treatment.

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