Plasma exosomal miR-181a-5p is linked to osteoporosis by mediating endothelial-osteoblast crosstalk and regulating bone remodeling.

To elucidate the correlation between plasma exosomal miR-181a-5p and osteoporosis (OP). Three independent case-control cohorts were recruited plasma exosomes were isolated to identify miRNAs associated with OP by using custom miRNA array and RT-qPCR. ROC curve was used to evaluate diagnostic performance of key miRNA. An endothelial cell (EC) line overexpressing miR-181a-5p was constructed via lentivirus (LV) infection. Incubation of EC-exosomes (EC-Exos) with the MC3T3-E1 osteoblasts, as well as a co-culture of ECs with MC3T3-E1 cells, were used to test the effects of miR-181a-5p on osteoblast functions (proliferation, differentiation, and activity) in vitro. The miR-181a-5p target genes were predicted, and verified by dual-luciferase reporter assay. Plasma exosomal miR-181a-5p abundance was consistently up-regulated in OP patients across three independent cohorts. Transfection-induced up-regulation of miR-181a-5p inhibited OPG and ZFP36L1 genes activity via targeting 3'UTR, and significantly inhibited osteoblastic gene expression (ALP, COL1A1, RUNX2 and OCN), differentiation (ALP activity), and bone formation (calcification) in MC3T3-E1 cells. ECs may represent one important source of circulating exosomal miR-181a-5p. Osteoblast gene expression and differentiation were significantly inhibited in MC3T3-E1 cells that had been either incubated with LV-miR-181a-5p-ECs-Exos or co-cultured with LV-miR-181a-5p-ECs. These findings not only reveal a novel EC-osteoblast communication pathway but also suggest that plasma exosomal miR-181a-5p is a promising diagnostic biomarker and a potential therapeutic target for OP.