Elsevier

Bone

Volume 79, October 2015, Pages 43-51
Bone

Original Full Length Article
Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation

https://doi.org/10.1016/j.bone.2015.05.027Get rights and content
Under a Creative Commons license
open access

Highlights

  • A comprehensive analysis of 175 circulating microRNAs in patients with recent osteoporotic femoral fractures was performed.

  • Differential expression of three microRNA was confirmed in a validation cohort including 12 patients and 11 controls.

  • From the list of known circulating microRNAs in osteoporosis, 7 miRNAs were selected for functional characterization.

  • Five out of seven circulating miRNAs, which change in response to fracture or osteoporosis modulate osteogenic differentiation in vitro.

Abstract

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 and are known to take part in the control of bone formation and bone resorption. In addition, it is known that miRNAs are secreted by many cell types and can transfer “messages” to recipient cells. Thus, circulating miRNAs might not only be useful as surrogate biomarkers for the diagnosis or prognosis of pathological conditions, but could be actively modulating tissue physiology.

Therefore, the aim of this study was to test whether circulating miRNAs that exhibit changes in recent osteoporotic fracture patients could be causally related to bone metabolism.

In the first step we performed an explorative analysis of 175 miRNAs in serum samples obtained from 7 female patients with recent osteoporotic fractures at the femoral neck, and 7 age-matched female controls. Unsupervised cluster analysis revealed a high discriminatory power of the top 10 circulating miRNAs for patients with recent osteoporotic fractures. In total 6 miRNAs, miR-10a-5p, miR-10b-5p, miR-133b, miR-22-3p, miR-328-3p, and let-7g-5p exhibited significantly different serum levels in response to fracture (adjusted p-value < 0.05). These miRNAs were subsequently analyzed in a validation cohort of 23 patients (11 control, 12 fracture), which confirmed significant regulation for miR-22-3p, miR-328-3p, and let-7g-5p. A set of these and of other miRNAs known to change in the context of osteoporotic fractures were subsequently tested for their effects on osteogenic differentiation of human mesenchymal stem cells (MSCs) in vitro. The results show that 5 out of 7 tested miRNAs can modulate osteogenic differentiation of MSCs in vitro.

Overall, these data suggest that levels of specific circulating miRNAs change in the context of recent osteoporotic fractures and that such perturbations of “normal” levels might affect bone metabolism or bone healing processes.

Keywords

Osteoporosis
Circulating microRNA (miRNA)
Bone
Quantitative PCR (qPCR)
Osteogenic differentiation
Mesenchymal stem cells

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