Abstract
In this study, we used bioinformatics tools, and experiments with patient tissues and human mesenchymal stem cells (hMSCs) to identify differentially regulated genes (DEGs) and microRNAs (miRNAs) that promote postmenopausal osteoporosis. By analyzing the GSE56815 dataset from the NCBI GEO database, we identified 638 DEGs, including 371 upregulated and 267 downregulated genes, in postmenopausal women with low bone density. Enrichment and protein-protein interaction network analyses showed that TP53, RPS27A, and VEGFA were the top three hub genes with the highest degree of betweenness and closeness centrality. TargetScanHuman and DIANA software analyses and dual luciferase reporter assays confirmed that miR-16a-5p directly targets the 3’UTR of VEGFA. Postmenopausal patients with osteoporosis showed higher miR-16-5p and lower VEGFA levels than those without osteoporosis (n=10 each). VEGFA levels were higher in miR-16-5p knockdown hMSCs and were reduced in miR-16-5p-overexpressing hMSCs. mRNA expression of osteogenic markers, ALP, OCN, and RUNX2, as well as calcium deposition based on Alizarin red staining, correlated inversely with miR-16-5p levels and correlated positively with VEGFA levels. These findings suggest that miR-16-5p suppresses osteogenesis by inhibiting VEGFA expression and is a promising target for postmenopausal osteoporosis therapy.
Highlights
Osteoporosis is characterized by reduced bone mass and weakened bone micro-architecture, resulting in an increased risk of fractures [1]
Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis Table 2 and Figure 4 shows the results of the GO and KEGG pathway enrichment analysis of the hub genes www.aging-us.com and differentially regulated genes (DEGs) using Database for Annotation, Visualization and Integrated Discovery version (DAVID)
Xie et al reported that human mesenchymal stem cells (hMSCs) from osteoporosis patients show significantly higher TP53 expression; TP53, SP1 and CTNNB1 transcription factors regulate most of the upregulated DEGs [32]
Summary
Osteoporosis is characterized by reduced bone mass and weakened bone micro-architecture, resulting in an increased risk of fractures [1]. Osteoporosis is a common age-related disease in post-menopausal women and the elderly [2]. It affects the quality of life of nearly 200 million people worldwide and is a significant burden on the public healthcare systems [3]. 40% of women suffer from osteoporosis and sustain fractures of the hip, spine, or the forearm during their lifetime [4]. Recent studies have identified SQRDL and PPWD1 genes as risk factors that are associated with osteoporosis [6, 7]
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