Abstract
It is commonly observed that patients with bone fracture concomitant with traumatic brain injury (TBI) had significantly increased fracture healing, but the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) are known to play complicated roles in bone homeostasis, but their role in TBI accelerated fracture was rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatics analyses. Blood samples from three fracture-only patients, three fracture concomitant with TBI patients, and three healthy controls were harvested and were subsequently subjected to transcriptome lncRNA sequencing. Differentially expressed genes were identified, and pathway enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. High-dimensional data visualization by self-organizing map (SOM) machine learning was applied to further interpret the data. An xCell method was then used to predict cellular behavior in all samples based on gene expression profiles, and an lncRNA–cell interaction network was generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on TBI-related and damage repair-related pathways. SOM analyses revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune-related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly downregulated, while microvascular endothelial cells were predicted to be significantly upregulated in the Fr/TBI group, was the lowest and highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expressed lncRNAs related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells, and endothelial cells.
Highlights
Fractures, the most common injuries of the musculoskeletal system of humans, are a major cause of global mortality and disability [1]
To determine whether expressions of Long non-coding RNAs (lncRNAs) were changed in traumatic brain injury (TBI) accelerated fracture, an lncRNA-based transcriptome sequencing was performed
Among all identified lncRNAs (Figure 1B, Supplementary Table 1), the majority were large intergenic non-coding RNAs and antisense lncRNAs (Figure 1C). These differentially expressed mRNAs and lncRNAs were mainly involved in TBI-related and damage repair-related pathways
Summary
The most common injuries of the musculoskeletal system of humans, are a major cause of global mortality and disability [1]. The initial response of bone injury was vascular disruption-induced hematoma and clot formation at the fracture site This danger signal subsequently induces the infiltration of immune cells and the release of inflammatory cytokine, chemokines, and growth factors. TBI accelerated fracture healing was observed to be highly associated with changes in mesenchymal stem cells, cytokines and growth factors, hormones, and other substances like calcium and phosphate [9]. The present study was designed to identify differentially expressed lncRNA via high-throughput sequencing and to further determine their roles in TBI accelerated fracture healing by bioinformatics analysis. The sample size for this study was limited to three TBI concomitant with fracture patients These were randomly selected in accordance with the method of random number table based on the inclusion and exclusion criteria.
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