Abstract
The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (∼8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA-mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation.
Highlights
The osteoblast, a cell type of a mesenchymal origin, plays a major role in skeletal development and bone formation [1, 2]
In the process of human bone marrow-derived mesenchymal stem cells (BMSCs) osteogenic differentiation, the messenger RNAs (mRNAs) and protein expression levels of osteoblastic target genes, such as alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP-2), and platelet-derived factor alpha polypeptide (PDGF-a) at most time points increased significantly when compared with the values at 0 hour with maximum changes at 1 to 7 days (S1 Figure)
We found that 5 miRNAs were more than 2-fold change in exosomes isolated from BMSCs culture when compared with the maximum changes at 0.5 to 7 days with the values at 0 day. (Table 1)
Summary
The osteoblast, a cell type of a mesenchymal origin, plays a major role in skeletal development and bone formation [1, 2]. In the last two decades, progress in molecular and genetic research has uncovered various regulatory processes of osteoblast differentiation [1, 2, 4]. Central to this regulation are transcription factors; Runx, Osterix, and b-catenin are, to date, the transcription factors known to be essential for osteoblast differentiation [2]. Given the fact that the number of coding genes in vertebrates and invertebrates (which lack a skeleton) is comparable [7], there must be additional mechanisms for controlling skeletal development other than transcriptional regulation of gene expression
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