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. 2018 Mar 20;8(1):4867.
doi: 10.1038/s41598-018-22844-2.

Bone-related Circulating MicroRNAs miR-29b-3p, miR-550a-3p, and miR-324-3p and their Association to Bone Microstructure and Histomorphometry

Xaver Feichtinger  1   2   3 , Christian Muschitz  2 , Patrick Heimel  1   4   5 , Andreas Baierl  6 , Astrid Fahrleitner-Pammer  7 , Heinz Redl  1   4 , Heinrich Resch  2   8 , Elisabeth Geiger  9 , Susanna Skalicky  9 , Rainer Dormann  2 , Fabian Plachel  2 , Peter Pietschmann  10 , Johannes Grillari  9   11 , Matthias Hackl  12 , Roland Kocijan  1   2
Affiliations

Bone-related Circulating MicroRNAs miR-29b-3p, miR-550a-3p, and miR-324-3p and their Association to Bone Microstructure and Histomorphometry

Xaver Feichtinger et al. Sci Rep. .

Abstract

The assessment of bone quality and the prediction of fracture risk in idiopathic osteoporosis (IOP) are complex prospects as bone mineral density (BMD) and bone turnover markers (BTM) do not indicate fracture-risk. MicroRNAs (miRNAs) are promising new biomarkers for bone diseases, but the current understanding of the biological information contained in the variability of miRNAs is limited. Here, we investigated the association between serum-levels of 19 miRNA biomarkers of idiopathic osteoporosis to bone microstructure and bone histomorphometry based upon bone biopsies and µCT (9.3 μm) scans from 36 patients. Four miRNAs were found to be correlated to bone microarchitecture and seven miRNAs to dynamic histomorphometry (p < 0.05). Three miRNAs, namely, miR-29b-3p, miR-324-3p, and miR-550a-3p showed significant correlations to histomorphometric parameters of bone formation as well as microstructure parameters. miR-29b-3p and miR-324-p were found to be reduced in patients undergoing anti-resorptive therapy. This is the first study to report that serum levels of bone-related miRNAs might be surrogates of dynamic histomorphometry and potentially reveal changes in bone microstructure. Although these findings enhance the potential value of circulating miRNAs as bone biomarkers, further experimental studies are required to qualify the clinical utility of miRNAs to reflect dynamic changes in bone formation and microstructure.

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Conflict of interest statement

Roland Kocijan, Xaver Feichtinger, Patrick Heimel, Christian Muschitz, Andreas Baierl, Astrid Fahrleitner-Pammer, Heinrich Resch, Rainer Dormann, Peter Pietschmann, and Fabian Plachel state that they have no conflicts of interest. Matthias Hackl and Johannes Grillari are co-founders of TAmiRNA. Matthias Hackl, Elisabeth Geiger, and Susanna Skalicky are employed by TAmiRNA GmbH. Johannes Grillari and Heinz Redl are scientific advisors to TAmiRNA. Matthias Hackl and Johannes Grillari hold patents related to the use of circulating microRNAs as biomarkers for bone diseases.

Figures

Figure 1
Figure 1
Cortical and trabecular bone microstructure in male idiopathic osteoporosis. Images of two male patients were chosen for this figure to highlight the heterogeneity of bone quality within the study groups. The variation of bone structure parameters was similar in premenopausal and postmenopausal women. The heterogeneity of bone microstructure within the subgroups is further reflected by the high standard deviation and the absence of significant findings between the subgroups (Table 2). Left, high cortical porosity (Ct.Po) and low trabecular bone volume (BV/TV); right, low Ct.Po and high BV/TV. (A) Ct.Po, 2-D analysis; (B) Ct.Po. 3-D reconstruction; (C) BV/TV, 2-D analysis; (D) BV/TV, 3-D reconstruction.
Figure 2
Figure 2
Volcano plot of Spearman coefficients versus p-values. (a) Bone histomorphometry: seven bone histomorphometric parameters were correlated to serum levels of 19 microRNAs. Spearman coefficients (x-axis) and p-values (y-axis) are shown. Labels were added for those microRNAs where p-values for association were equal or below 0.05. (b) bone microstructure: an analogous analysis was performed for trabecular (BV/TV) and cortical porosity (Ct. Pos.). Likewise, microRNAs with p-values < 0.05 are labelled in the plot.
Figure 3
Figure 3
Scatterplots. Values and relationships between three miRNAs, miR-29b-3p, miR-324-3p, and miR-550a-3p, on the y-axis, and selected parameters from bone histomorphometry (MAR, BFR/BS, BS/BV) and microstructure (BV/TV, Ct. Po) on the x-axis, are shown. Spearman correlation coefficients and significance levels are shown in each plot. Red color signals p < 0.05. Linear trend lines have been added to plots with p < 0.05.
Figure 4
Figure 4
Boxplots. Distribution of the normalized delta-Cq values of (a) miR-29b-3p, (b) miR-324-3p, and (c) miR-550a-3p between treatment-naïve (Fracture/naive, n = 20) and bisphosphonate pre-treated subjects (Fracture/treatment (ART), n = 13) and are shown. As a reference, the normalized delta Cq-values in a matched healthy reference group are shown, which has been previously described (ref.). P-values for the difference between treated and untreated subjects with fracture derived from non-parametric Kruskal-Wallis tests.
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