Dataset Information

Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model.

ABSTRACT: BACKGROUND:We investigated the underlying molecular mechanisms of bone overgrowth after femoral fracture by using high-throughput bioinformatics approaches. METHODS:The gene expression profile of GSE3298 (accession number) was obtained from the Gene Expression Omnibus database. Sixteen femoral growth plate samples, including nine samples without fracture and seven fracture samples for seven time points, were used for analysis. The Limma package was applied to identify differentially expressed genes (DEGs) between fractured and intact samples. The DAVID online tool was used for Gene ontology functional and pathway enrichment analysis. A protein-protein interaction (PPI) network established by String software was used to identify interactions between significant DEGs, and network modules were detected using plug-in MCODE. Additionally, a transcription regulatory network was constructed based on the ENCODE Project and PPI network. RESULTS:A total of 680 DEGs were screened in fractured femoral growth plate samples compared with controls, including 238 up- and 442 down-regulated genes. These DEGs were significantly involved in the calcium signaling pathway and cancer pathway. A PPI network was constructed with 167 nodes and 233 edges, and module analysis demonstrated that CCL2, CSF2, NOS2, and DLC1 may stimulate bone overgrowth after femoral fracture via anti-apoptosis-related functions. A transcription regulatory network was constructed with 387 interacting pairs, and overlapping nodes were significantly enriched in intracellular signaling cascade and regulation of cell proliferation, among others. CONCLUSIONS:Bone overgrowth was associated with changes in the expression of identified DEGs such as CCL2, NOS2, CSF2, and DLC1 in the femoral head. They may be important in regulating bone overgrowth via the anti-apoptosis of osteoblasts.

SUBMITTER: Liu C

PROVIDER: S-EPMC5240322 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model.

Liu Chibing C Liu Yanting Y Zhang Weizhong W Liu Xiuxin X

Journal of orthopaedic surgery and research 20170117 1

<h4>Background</h4>We investigated the underlying molecular mechanisms of bone overgrowth after femoral fracture by using high-throughput bioinformatics approaches.<h4>Methods</h4>The gene expression profile of GSE3298 (accession number) was obtained from the Gene Expression Omnibus database. Sixteen femoral growth plate samples, including nine samples without fracture and seven fracture samples for seven time points, were used for analysis. The Limma package was applied to identify differential ...[more]

PMID: 28095896

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Project description:The pathophysiology of the osteomalacia in X-linked hypophosphatemia is uncertain. In this project, genomic DNA microarrays were used to identify novel genes with abnormal mRNA expression levels in mice with the dominant Hyp mutation of the Phex gene. Femoral shafts from five-week-old C57BL/6J mice, male and female, normal and Hyp (hemizygous male and heterozygous female), were flushed with saline to remove the marrow. RNA was extracted from each bone, pooled between two mice for each array, processed to cRNA, and hybridized to Affymetrix Mouse 430 2.0 GeneChip microarrays with probe sets for 45,101 genes. Twenty microarrays (40 mice) were done with 5 arrays for each treatment group (normal male, Hyp male, normal female and Hyp female). For each gene, factorial analysis of variance was performed for the main effects of genotype (normal vs. Hyp), sex (male vs. female), and genotype-by-sex interaction. The mRNA levels for 54 % of the genes on each array were scored as present. At P < 0.01, 2,635 genes were significant for genotype, 1,488 for sex, and 509 for genotype-by-sex interaction. There were two probes sets for the Phex gene. Probe 1450445, at the 3’ end of the coding sequence, was low in normal samples (246 ± 37 (10), mean ± SEM (n)) and absent in Hyp samples. Probe 1421979, at the far 3’ end of the untranslated region of the cDNA, 3,000 base pairs from the coding sequence, was high in normal mice (3,915 ± 315 (10); 8x brighter than the average gene), undetectable in Hyp males, and 725 ± 93 (5) in Hyp females. Both probe sets were scored as absent in kidney tissue. In Hyp bone, male and female, there was significant down-regulation of markers of osteoblasts and bone matrix synthesis with significant up-regulation of markers of blood vessel formation and cytoskeleton. No prominent skeletal gene was up-regulated in Hyp to attempt to compensate for the low skeletal mineralization. The genes with significant genotype-by-sex interaction did not show a marked fold difference between male and female Hyp mice. In conclusion, male and female Hyp mice showed similar depression of mRNA levels of genes related to bone synthesis in the femoral shaft. There was a high signal level from probes for a sequence in the 3’ untranslated region of the Phex gene of normal, but not Hyp, mice, suggesting the need for further study of the molecular organization of this gene. Keywords: 2x2 factorial design with complete blocks

Project description:The most reliable predictor of future fracture risk is a previous fracture of any kind. The etiology of this increased fracture risk is not fully known, but it is possible that fracture initiates systemic bone loss, leading to greater fracture risk at all skeletal sites. In this study, we investigated systemic bone loss and recovery after femoral fracture in young (3-month-old) and middle-aged (12-month-old) mice. Transverse femur fractures were created using a controlled impact, and whole-body bone mineral density (BMD), trabecular and cortical microstructure, bone mechanical properties, bone formation and resorption rates, mouse voluntary movement, and systemic inflammation were quantified at multiple time points post-fracture. We found that fracture led to decreased whole-body BMD in both young and middle-aged mice 2 weeks post-fracture; this bone loss was recovered by 6 weeks in young but not middle-aged mice. Similarly, trabecular bone volume fraction (BV/TV) of the L5 vertebral body was significantly reduced in fractured mice relative to control mice 2 weeks post-fracture (-11% for young mice, -18% for middle-aged mice); no significant differences were observed 6 weeks post-fracture. At 3 days post-fracture, we observed significant increases in serum levels of interleukin-6 and significant decreases in voluntary movement in fractured mice compared with control mice, with considerably greater changes in middle-aged mice than in young mice. At this time point, we also observed increased osteoclast number on L5 vertebral body trabecular bone of fractured mice compared with control mice. These data show that systemic bone loss occurs after fracture in both young and middle-aged mice, and recovery from this bone loss may vary with age. This systemic response could contribute to increased future fracture risk after fracture; these data may inform clinical treatment of fractures with respect to improving long-term skeletal health. © 2018 American Society for Bone and Mineral Research.

Dataset Information

Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model.

Publications

Screening for potential genes associated with bone overgrowth after mid-shaft femur fracture in a rat model.

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