title: Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro.
abstract: Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n = 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Heilmeier
authors.affiliation: TAmiRNA GmbH, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hackl
authors.affiliation: Evercyte GmbH, Vienna, Austria.
authors.forename: Susanna
authors.initials: S
authors.lastname: Skalicky
authors.affiliation: Evercyte GmbH, Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Weilner
authors.affiliation: Department of Molecular Diagnostics, Austrian Institute of Technology (AIT), Vienna, Austria.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schroeder
authors.affiliation: Department of Molecular Diagnostics, Austrian Institute of Technology (AIT), Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Vierlinger
authors.affiliation: Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.|Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Austria.
authors.forename: Janina M
authors.initials: JM
authors.lastname: Patsch
authors.affiliation: Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baum
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Forschungszentrum für Traumatologie der Allgemeinen Unfallversicherungsanstalt (AUVA) Research Center, Linz/Vienna, Austria.
authors.forename: Eleni
authors.initials: E
authors.lastname: Oberbauer
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Lobach
authors.affiliation: Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Burghardt
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ann V
authors.initials: AV
authors.lastname: Schwartz
authors.affiliation: Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.affiliation: Musculoskeletal Quantitative Imaging Research Group, Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Link
mesh_terms: D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000473:pathology*; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D005260:Female; D050723:Fractures, Bone / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D010012:Osteogenesis / Q000235:genetics*; D058866:Osteoporotic Fractures / Q000097:blood / Q000235:genetics; D017698:Postmenopause / Q000097:blood*
chemical_list: D035683:MicroRNAs
keywords: CELLS OF BONE; DIABETIC OSTEOPATHY; EPIGENETICS; FRACTURE RISK ASSESSMENT; OSTEOPOROSIS; STROMAL/STEM CELLS