Dataset Information

Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling.

ABSTRACT: To compare differentially expressed genes (DEGs) mediating osteoarthritis (OA) in knee cartilage and in normal knee cartilage in a rat model of OA and to identify their impact on molecular pathways associated with OA.A gene expression profile was downloaded from the Gene Expression Omnibus database. Analysis of DEGs was carried out using GEO2R. Enrichment analyses were performed on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway using the Search Tool for the Retrieval of Interacting Genes database (http://www.string-db.org/). Subsequently, the regulatory interaction network of OA-associated genes was visualized using Cytoscape software (version 3.4.0; www.cytoscape.org).In the gene expression profile GSE103416, a total of 99 DEGs were identified. Among them, 76 DEGs (76.77%) were overexpressed, and the remaining 23 DEGs (23.23%) were underexpressed. GO and pathway enrichment analyses of target genes were performed. Using gene-gene interaction network analysis, relevant core genes, including MET, UBB, GNAI3, and GNA13, were shown to hold a potential relationship with the development of OA in cartilage. Using quantitative real-time PCR, the Gna13/cGMP-PKG signaling pathway was identified as a potential research target for therapy and for further understanding the development of OA.The results of the present study provide a comprehensive understanding of the roles of DEGs in knee cartilage in relation to the development of OA.

SUBMITTER: Ren YM

PROVIDER: S-EPMC6037600 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling.

Ren Yi Ming YM Zhao Xin X Yang Tao T Duan Yuan Hui YH Sun Yun Bo YB Zhao Wen Jun WJ Tian Meng Qiang MQ

Yonsei medical journal 20180801 6

<h4>Purpose</h4>To compare differentially expressed genes (DEGs) mediating osteoarthritis (OA) in knee cartilage and in normal knee cartilage in a rat model of OA and to identify their impact on molecular pathways associated with OA.<h4>Materials and methods</h4>A gene expression profile was downloaded from the Gene Expression Omnibus database. Analysis of DEGs was carried out using GEO2R. Enrichment analyses were performed on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pa ...[more]

PMID: 29978613

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Project description:OBJECTIVE: To analyze genome-wide changes in chondrocyte gene expression in a surgically induced model of early osteoarthritis (OA) in rats, to assess the similarity of this model to human OA, and to identify genes and mechanisms leading to OA pathogenesis. METHODS: OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression. Expression patterns of selected dysregulated genes, including Col2a1, Mmp13, Adamts5, Ctsc, Ptges, and Cxcr4, were validated by real-time polymerase chain reaction, immunofluorescence, or immunohistochemistry 2, 4, and 8 weeks after surgery. RESULTS: After normalization, comparison of OA and sham-operated samples showed 1,619 differentially expressed probe sets with changes in their levels of expression >/=1.5-fold, 722 with changes >/=2-fold, 135 with changes >/=4-fold, and 20 with changes of 8-fold. Dysregulated genes known to be involved in human OA included Mmp13, Adamts5, and Ptgs2, among others. Several dysregulated genes (e.g., Reln, Phex, and Ltbp2) had been identified in our earlier microarray study of hypertrophic chondrocyte differentiation. Other genes involved in cytokine and chemokine signaling, including Cxcr4 and Ccl2, were identified. Changes in gene expression were also observed in the contralateral knee, validating the sham operation as the appropriate control. CONCLUSION: Our results demonstrate that the animal model mimics gene expression changes seen in human OA, supporting the relevance of newly identified genes and pathways to early human OA. We propose new avenues for OA pathogenesis research and potential targets for novel OA treatments, including cathepsins and cytokine, chemokine, and growth factor signaling pathways, in addition to factors controlling the progression of chondrocyte differentiation. Experiment Overall Design: OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees, 28 days post-surgery. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression.

Project description:Background: Osteoarthritis (OA) is one of the main causes of disability in the elderly population, accompanied by a series of underlying pathologic changes, such as cartilage degradation, synovitis, subchondral bone sclerosis, and meniscus injury. The present study aimed to identify key genes, signaling pathways, and miRNAs in knee OA associated with the entire joint components, and to explain the potential mechanisms using computational analysis. Methods: The differentially expressed genes (DEGs) in cartilage, synovium, subchondral bone, and meniscus were identified using the Gene Expression Omnibus 2R (GEO2R) analysis based on dataset from GSE43923, GSE12021, GSE98918, and GSE51588, respectively and visualized in Volcano Plot. Venn diagram analyses were performed to identify the overlapping DEGs (overlapping DEGs) that expressed in at least two types of tissues mentioned above. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) analysis, and module analysis were conducted. Furthermore, qRT-PCR was performed to validate above results using our clinical specimens. Results: As a result, a total of 236 overlapping DEGs were identified, of which 160 were upregulated and 76 were downregulated. Through enrichment analysis and constructing the PPI network and miRNA-mRNA network, knee OA-related key genes, such as HEY1, AHR, VEGFA, MYC, and CXCL12 were identified. Clinical validation by qRT-PCR experiments further supported above computational results. In addition, knee OA-related key miRNAs such as miR-101, miR-181a, miR-29, miR-9, and miR-221, and pathways such as Wnt signaling, HIF-1 signaling, PI3K-Akt signaling, and axon guidance pathways were also identified. Among above identified knee OA-related key genes, pathways and miRNAs, genes such as AHR, HEY1, MYC, GAP43, and PTN, pathways like axon guidance, and miRNAs such as miR-17, miR-21, miR-155, miR-185, and miR-1 are lack of research and worthy for future investigation. Conclusion: The present informatic study for the first time provides insight to the potential therapeutic targets of knee OA by comprehensively analyzing the overlapping genes differentially expressed in multiple joint components and their relevant signaling pathways and interactive miRNAs.

Project description:BackgroundJoint hemorrhage is caused by trauma, ligament reconstruction surgery, and bleeding disorders such as hemophilia. Recurrence of hemorrhage in the joint space induces hemosiderotic synovitis and oxidative stress, resulting in both articular cartilage degeneration and arthropathy. Joint immobilization is a common treatment option for articular fractures accompanied by joint hemorrhage. Although joint hemorrhage has negative effects on the articular cartilage, there is no consensus on whether a reduction in joint hemorrhage would effectively prevent articular cartilage degeneration. The purpose of this study was to investigate the effect of joint hemorrhage combined with joint immobilization on articular cartilage degeneration in a rat immobilized knee model.MethodsThe knee joints of adult male rats were immobilized at the flexion using an internal fixator from 3 days to 8 weeks. The rats were randomly divided into the following groups: immobilized blood injection (Im-B) and immobilized-normal saline injection (Im-NS) groups. The cartilage was evaluated in two areas (contact and non-contact areas). The cartilage was used to assess chondrocyte count, Modified Mankin score, and cartilage thickness. The total RNA was extracted from the cartilage in both areas, and the expression of metalloproteinase (MMP)-8, MMP-13, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α was measured by quantitative real-time polymerase chain reaction.ResultsThe number of chondrocytes in the Im-B group significantly decreased in both areas, compared with that in the Im-NS group. Modified Mankin score from 4 to 8 weeks of the Im-B group was significantly higher than that of the Im-NS group only in the contact area. The expression of MMP-8 and MMP-13 from 2 to 4 weeks and TNF-α from 2 to 8 weeks significantly increased in the Im-B group compared with those in the Im-NS group, but there was no significant difference in IL-1β expression.ConclusionsThe results showed that joint hemorrhage exacerbated immobilization-induced articular cartilage degeneration. Drainage of a joint hemorrhage or avoidance of loading may help prevent cartilage degeneration during joint immobilization with a hemorrhage.

Dataset Information

Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling.

Publications

Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling.

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