Abstract
The pathogenesis of osteoporosis is considered extremely intricate. Osteoblast differentiation and angiogenesis can greatly affect bone development and formation, given their coupling role in these processes. Exosome-mediated miRNA regulates cellular senescence, proliferation, and differentiation. However, whether senescent osteoblasts can regulate the senescence of vascular endothelial cell by miRNA through exosomal pathway remains unclear. In this study, senescent osteoblasts could regulate endothelial cell function, promote cell senescence and apoptosis, and decrease cell proliferation via exosomal pathway. miR-139-5p showed high expression in senescent osteoblasts and their exosomes. After senescent osteoblast-derived exosome treatment, miR-139-5p was also upregulated in endothelial cells. Furthermore, transfection of miR-139-5p mimic promoted the senescence and apoptosis of vascular endothelial cells and inhibited their proliferation and migration, whereas transfection of miR-139-5p inhibitor rescued the effect of D-galactose. Using double luciferase assay, TBX1 was confirmed to be a direct target gene of miR-139-5p. In conclusion, senescent osteoblast-derived exosome-mediated miR-139-5p regulated endothelial cell function via exosomal pathway. Our study revealed the role of osteoblast-derived exosomes in the bone environment during aging, providing a clue for inventing a new target therapy.
Highlights
Considering the close relationship between osteogenesis and angiogenesis, an increasing number of studies started investigating the relationship between osteoporosis, which is a very common disease, and angiogenesis [1]
The exosome membrane primarily comprises lipids and proteins that carry a variety of proteins, nucleic acids, microRNA, and mRNA, which can be absorbed by other cells in order to regulate recipient cells [6]. miRNAs are defined as noncoding, single-stranded RNA molecules of about 22 nucleotides in length that mediate posttranscriptional gene silencing by binding to the 3′-UTR or open reading frame region of target mRNA, which can affect the generation of many proteincoding genes identified to be participating in the regulation of several organismal life activities, such as cell proliferation, differentiation, migration, and even disease progression [7]
The results showed that the senescence and apoptosis positive rate increased and the cell proliferation rate decreased in the endothelial cells cocultured with senescent osteoblasts (Figures 2(a), 2(b), and 2(c))
Summary
Considering the close relationship between osteogenesis and angiogenesis, an increasing number of studies started investigating the relationship between osteoporosis, which is a very common disease, and angiogenesis [1]. The widely accepted relationship between these two is that the reduction of angiogenesis causes osteoporosis and the promotion of local angiogenesis alleviates it [2] and the bone matrix can secrete proangiogenic endothelial cell factor and promotes angiogenesis in reverse, which provides the necessary nutrients and regulators for osteogenesis [3,4,5]. MiRNAs are defined as noncoding, single-stranded RNA molecules of about 22 nucleotides in length that mediate posttranscriptional gene silencing by binding to the 3′-UTR or open reading frame region of target mRNA, which can affect the generation of many proteincoding genes identified to be participating in the regulation of several organismal life activities, such as cell proliferation, differentiation, migration, and even disease progression [7]. Owing to the transport capabilities of vesicles, the role of miRNAs in exosomes is being increasingly appreciated
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