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The micro-RNA signature of hypertrophic callus-formation in bone fractures accompanied with traumatic brain injury.

ABSTRACT: Long-bone-fractures occasionally heal with hypertrophic callus formation when patients suffer a concomitant traumatic brain injury. Although this phenomenon is known for decades, the causal factors are still poorly understood and no feasible markers are currently available to predict the exuberant bone-mass-formation at an early timepoint after injury. In this study, we used small-RNA-seq, bioinformatic analyses and in vitro assays to identify a set of micro-RNAs in serum of hypertrophic callus patients that serve as potential biomarkers. The identified miRNAs are highly expressed in the human brain, primarily in the pituitary gland, they are differentially expressed during osteogenic differentiation of bone-marrow-derived mesenchymal stem cells and they regulate mRNA-targets, involved in bone-related pathways, such as RANK/RANKL, BMP/RUNX2, PI3K-AKT and Wnt/beta-catenin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294842 | GEO | 2025/04/21

REPOSITORIES: GEO

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Project description:Osteoporosis is the consequence of altered bone metabolism resulting in the systemic reduction of bone strength and increased risk of fragility fractures. MicroRNAs (miRNAs) regulate gene expression on a post-transcriptional level are known to take part in the control of bone formation and bone resorption. Recently, targeted secretion of miRNAs from cells originating from various tissues has been described, which allows for their minimal-invasive detection in serum/plasma and use as biomarkers for presence and progression of pathological conditions. One pilot study has reported circulating miRNAs in serum and tissue of fracture patients. However, further studies are required to explore whether a dysbalance in bone homeostasis of fracture patients can reliably be reflected by specific circulating miRNAs, and whether these miRNAs might serve as drugable targets. Here, we report results from a comprehensive multiplex study of 175 miRNAs in serum samples obtained from 7 patients with osteoporotic fractures at the femoral neck, and 7 age-matched controls. Following elaborate quality control statistical analysis of this exploratory dataset identified 9 microRNAs with altered serum levels in response to fracture (adjusted p-value < 0.1). Of these, hsa-miR-10a/b gave excellent discrimination of both groups (AUC = 1.0), and clustering of samples based on the top10 miRNAs confirmed the high discriminatory power of circulating microRNAs for osteoporotic fractures. In the next step 3 miRNAs with unknown roles in osteogenic differentiation and 4 miRNA from a previous study were tested for their effects on osteogenic differentiation. Of these, 3 miRNAs showed robust effects on osteogenic differentiation. Overall, these data provide important insights into changes in serum miRNA in post-traumatic patients. Future studies will show, whether this knowledge can be used to improve current diagnostic methodologies to predict fracture risk and design novel treatment strategies for osteoporosis patients. Two groups with n=7 per group; one groups represents cases with osteoporotic fractures, the control group is age-matched without fractures

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The micro-RNA signature of hypertrophic callus-formation in bone fractures accompanied with traumatic brain injury.

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