Abstract
This study was designed to evaluate the effects of strontium on the expression levels of microRNAs (miRNAs) and to explore their effects on skeletal cell proliferation, differentiation, adhesion, and apoptosis. The targets of these miRNAs were also studied. Molecular cloning, cell proliferation assay, cell apoptosis assay, quantitative real-time PCR, and luciferase reporter assay were used. Strontium altered the expression levels of miRNAs in vitro and in vivo. miR-9-5p, miR-675-5p, and miR-138-5p impaired skeletal cell proliferation, cell differentiation and cell adhesion. miR-9-5p and miR-675-5p induced MC3T3-E1 cell apoptosis more specifically than miR-138-5p. miR-9-5p, miR-675-5p, and miR-138-5p targeted glycogen synthase kinase 3 β (GSK3β), ATPase Aminophospholipid Transporter Class I Type 8A Member 2 (ATP8A2), and Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (EIF4EBP1), respectively. Low-density lipoprotein receptor-related protein 5 (LRP5) played a positive role in skeletal development. miR-9-5p, miR-675-5p, and miR-138-5p damage strontium and LRP5-mediated skeletal cell proliferation, differentiation, and adhesion, and induce cell apoptosis by targeting GSK3β, ATP8A2, and EIF4EBP1, respectively.
Highlights
Strontium ranelate is a drug used for treating osteoporosis
MiR-138 inhibits the osteogenic differentiation of mesenchymal stem cells [3]. miR-370 remarkably attenuates BMP-2-induced pre-osteoblast differentiation [4]. miRNAs inhibit gene expression through binding to the 31-untranslated region (31UTR) of target mRNAs
Transfection of a hairy/enhancer-of-split related with YRPW motif protein 1 (Hey1) expression plasmid reversed the upregulation of differentiation markers in the MC3T3-E1 cells [10]
Summary
Strontium ranelate is a drug used for treating osteoporosis. The effects of strontium result in increased bone formation and decreased bone resorption [1]. Wnt signaling pathways play important roles in bone formation. Sclerostin has anti-anabolic effects on skeletal development and inhibits osteoblast differentiation and bone formation [7]. The inhibition of the Wnt signaling pathways results in decreased bone formation [9]. Transfection of a hairy/enhancer-of-split related with YRPW motif protein 1 (Hey1) expression plasmid reversed the upregulation of differentiation markers in the MC3T3-E1 cells [10]. This revealed the importance of Hey as a potent negative regulator of osteogenesis in regulating osteoblastic differentiation. We studied the potential targets of three important miRNAs and the roles LRP5 played in bone formation
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