Global miRNA expression and correlation with mRNA levels in primary human bone cells

Abstract

MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNAexpression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, α1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery

“…This finding is in contradiction to the generally expected repressive effect of miRNAs on target expression. Nevertheless, positive correlations have also been described in earlier studies on miRNA gene interactions, and thus the function of miRNAs may not be only repressive 21 . Since miRNAs are interwoven into complex regulatory networks, a suppression of a signaling mediator can lead to the transcription of a target gene, and consequently, result in a positive correlation 22 .…”

Role of microRNAs in progenitor cell commitment and osteogenic differentiation in health and disease (Review)

“…Altered patterns of miRNA expression have been shown in bone-related pathologies, which may jeopardize progenitor cell commitment and osteogenic differentiation. miR-29b is known to have an important regulatory role in osteoblast differentiation, as it targets cOL1A1 and SPARc (osteonectin) mRNAs (51). As osteoblasts mature, miR-29b attenuates the expression of collagen genes, allowing the organization of collagen fibrils for subsequent mineralization.…”

Novel microRNAs are associated with population divergence in transcriptional response to thermal stress in an intertidal copepod

“…When certain genes require increased transcription during periods of cellular stress, their repressor miRNAs are downregulated, and vice versa. Yet, studies have shown that as a miRNA is upregulated, its target mRNAs may also show transcription increase, highlighting the complexity of miRNA‐mRNA regulatory dynamics (Laxman et al, ; Nunez‐Iglesias, Liu, Morgan, Finch, & Zhou, ; Vasudevan, Tong, & Steitz, ). Such counter‐intuitive positive correlations may be the result of downstream feedbacks (Martinez, Ow, & Barrasa, ).…”