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Potential Genes and Pathways Associated with Heterotopic Yang et al. Journal of Orthopaedic Surgery and Research (2021) 16:499 https://doi.org/10.1186/s13018-021-02658-1 RESEARCH ARTICLE Open Access Potential genes and pathways associated with heterotopic ossification derived from analyses of gene expression profiles Zhanyu Yang1,2, Delong Liu1,2, Rui Guan1, Xin Li1, Yiwei Wang1 and Bin Sheng1,2* Abstract Background: Heterotopic ossification (HO) represents pathological lesions that refer to the development of heterotopic bone in extraskeletal tissues around joints. This study investigates the genetic characteristics of bone marrow mesenchymal stem cells (BMSCs) from HO tissues and explores the potential pathways involved in this ailment. Methods: Gene expression profiles (GSE94683) were obtained from the Gene Expression Omnibus (GEO), including 9 normal specimens and 7 HO specimens, and differentially expressed genes (DEGs) were identified. Then, protein– protein interaction (PPI) networks and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for further analysis. Results: In total, 275 DEGs were differentially expressed, of which 153 were upregulated and 122 were downregulated. In the biological process (BP) category, the majority of DEGs, including EFNB3, UNC5C, TMEFF2, PTH2, KIT, FGF13, and WISP3, were intensively enriched in aspects of cell signal transmission, including axon guidance, negative regulation of cell migration, peptidyl-tyrosine phosphorylation, and cell-cell signaling. Moreover, KEGG analysis indicated that the majority of DEGs, including EFNB3, UNC5C, FGF13, MAPK10, DDIT3, KIT, COL4A4, and DKK2, were primarily involved in the mitogen-activated protein kinase (MAPK) signaling pathway, Ras signaling pathway, phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway, and Wnt signaling pathway. Ten hub genes were identified, including CX3CL1, CXCL1, ADAMTS3, ADAMTS16, ADAMTSL2, ADAMTSL3, ADAMTSL5, PENK, GPR18, and CALB2. Conclusions: This study presented novel insight into the pathogenesis of HO. Ten hub genes and most of the DEGs intensively involved in enrichment analyses may be new candidate targets for the prevention and treatment of HO in the future. Keywords: Heterotopic ossification, Bioinformatic analysis, Differentially expressed genes, Protein–protein interaction, Functional enrichment analysis * Correspondence: [email protected] 1Department of Orthopaedics and Traumatology, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, No. 61 Jiefang West Road, Changsha, Hunan 410000, People’s Republic of China 2Hunan Emergency Center, No. 90 Pingchuan Road, Changsha, Hunan 410000, People’s Republic of China © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yang et al. Journal of Orthopaedic Surgery and Research (2021) 16:499 Page 2 of 10 Background Methods Heterotopic ossification (HO) represents pathological le- Microarray data resource sions, referred to as the development of heterotopic bone A gene expression profile dataset (GSE94683), GSE94683 in extraskeletal tissues around joints, which often occurs [15], a gene expression profile dataset obtained from a in the elbow, thigh, pelvis, and shoulder [1, 2]. The clinical public genomics data repository (GEO database, http:// manifestations were altered with the progression of the www.ncbi.nlm.nih.gov/geo/), was produced on the disease. Local pain, tenderness, swelling, and stiffness of GPL10630 Agilent-021531 Whole Human Genome Oligo the involved joints were present in the early stage of HO. Microarray 4x44K. According to the annotation informa- At the end of the disease, patients even present with tion in the platform, the probes were alternated into cor- complete ankyloses, which seriously damages their quality responding gene symbols. GSE94683 contains 9 normal of life [3]. The specific causes of HO were still uncertain. specimens and 7 HO specimens. HO specimens were ob- It is generally believed that the occurrence of HO is re- tained from patients with injuries at Garches Hospital, lated to genetic susceptibility and severe trauma. Progres- Garches, France. Healthy specimens were obtained from sive ossifying fibrous dysplasia (FOP), a genetic hereditary patients after total hip surgery at Blois Hospital (Blois, form of HO, is extremely rare, with a prevalence of ap- France) and at Centre de Transfusion Sanguine des proximately 1:2,000,000 in the population [4–7]. However, Armées (Percy Hospital, Clamart, France). there was a much higher incidence of HO following soft- tissue trauma, amputations, and central nervous system Data processing and identification of DEGs injury, such as cerebral anoxia, encephalitis, traumatic Principal components analysis (PCA) and normalization brain injuries, and spinal cord lesions [8, 9]. were performed by ggbiplot and the preprocessCore At present, the only effective way to treat HO is surgical package in R. After the preprocessing of the datasets, the resection of ossified tissue. Since HO is prone to recur- identification of DEGs was processed using multiple lin- rence, this method is only temporarily effective [10]. ear regression models via the limma package of R lan- Moreover, when the ossification tissue invades the large guage. A probe without any corresponding gene symbol blood vessels and nerves, the complication rate caused by was eliminated, and a gene with many probes was aver- resection is also increased. Studies have shown that HO is aged. All DEGs and the top 30 DEGs were demonstrated a disease with unknown pathogenesis, inadequate preven- via a volcano plot, which was performed by the ggplot2 tion and treatment, and a high disability rate [11]. There- package. DEGs were screened by using classical t test fore, to find a more effective therapeutic method, we need and |Log2(FoldChange)| > 2 and adj. P < 0.05 was de- to better understand the pathogenesis of HO [12]. fined as a threshold and criteria for the identification of Recently, translational medicine has provided a new statistically significant DEGs. The relative expression way of thinking that connects basic medical research values of total DEGs and the top 30 upregulated and with clinical treatment [13]. Bioinformatics based on downregulated DEGs, which were extracted from the genomic genetics and omics chips has a close interaction gene expression profile, were demonstrated by the hier- with systems medicine theory and automatic communi- archical clustering heatmaps via the pheatmap package cation technology, which speeds up the industrialization of R language. process of the transformation from scientific research to clinical application. Its application in orthopedics will Functional enrichment analysis for DEGs also lead to the rapid shortening of the distance between KEGG is a data reservoir for unravelling advanced bio- foundation and clinic and a new generation of ortho- logical functions and pathways involved with genomic pedic surgeons [14]. The bioinformatics analysis of gene information [16]. GO is a tool for defining concepts or expression, which serves as a key technology in mechan- classifying gene biological functions by analyzing a large istic exploration, plays an important role in screening list of genes [17]. The Database for Annotation, gene mutations and studying genetic behavior. Visualization and Integrated Discovery (DAVID), a web- Our study screened out the genes differentially based database resource that explores gene data, facili- expressed in bone marrow mesenchymal stem cells tates researchers to reveal potential genetic significance (BMSCs) from HO, which were identified from a public [18]. DAVID was used to perform the GO and KEGG dataset. In this work, we sought to synthesize protein– enrichment analyses. The functional enrichment ana- protein interaction (PPI) network analysis and Gene lyses were processed via the ggplot2 package in R and Ontology (GO) and Kyoto Encyclopedia of Genes and demonstrated by bubble plots. Genomes (KEGG) enrichment analysis among DEGs to explore the potential mechanism of HO and candidate Integration of PPI network analysis gene targets, which may be used to prevent, alleviate and The Search Tool for the Retrieval of Interacting Genes even reverse the progression of HO. (STRING), an original online program that predicts the Yang et al. Journal of Orthopaedic Surgery and Research (2021) 16:499 Page 3 of 10 relationships and interactions among proteins involved DEGs in HO samples compared with control samples
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