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

Xaver Feichtinger,Heinrich Resch,Andreas Baierl,Susanna Skalicky,Rainer Dormann,Matthias Hackl,Patrick Heimel,Heinz Redl,Elisabeth Geiger,Christian Muschitz,Roland Kocijan,Fabian Plachel,Johannes Grillari,Astrid Fahrleitner-Pammer,Peter Pietschmann

doi:10.1038/s41598-018-22844-2

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.

Highlights

The assessment of both bone quality and the prediction of fracture risk is complex in IOP as areal bone mineral density and established bone turnover markers (BTM) do not sufficiently explain the increased fracture risk[4,5]
Microstructure analysis was performed by the Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in Vienna; bone histomorphometry by the Medical University of Graz (Department of Internal Medicine, Division of Endocrinology and Diabetes); and miRNA analysis by the University of Natural Resources and Life Sciences Vienna (Department of Biotechnology) and TAmiRNA GmbH
These results suggest that circulating microRNAs can deliver additional information on bone metabolism which is not reflected by BTMs

Summary

Introduction

The assessment of both bone quality and the prediction of fracture risk is complex in IOP as areal bone mineral density (aBMD) and established bone turnover markers (BTM) do not sufficiently explain the increased fracture risk[4,5]. The association between impaired trabecular and cortical bone architecture to low-trauma fractures was previously reported. Specific signatures of circulating miRNAs were identified after acute osteoporotic fractures: in postmenopausal patients with prevalent fracture, as well as in premenopausal and male IOP and postmenopausal women with low-trauma fractures[11,12,13]. The latter study reported a set of 19 miRNAs, which was consistently regulated in all three groups (three up-regulated and 16 down-regulated miRNAs in the fracture groups) These miRNAs were excellent discriminators of patients with low-traumatic fractures, regardless of age and gender. We hypothesized that the complex pattern of IOP could be characterized by (i) bone microstructure and that there would be (ii) a significant association to serum levels of previously reported miRNAs

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Conclusion