title: 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, mRNA-expression 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.
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden Science for Life Laboratory, Department of Medical Sciences, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
authors.forename: Navya
authors.initials: N
authors.lastname: Laxman
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Carl-Johan
authors.initials: CJ
authors.lastname: Rubin
authors.affiliation: Department of Surgical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Mallmin
authors.affiliation: Department of Surgical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Nilsson
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1 Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1 Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden Science for Life Laboratory, Department of Medical Sciences, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kindmark
mesh_terms: D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: differential expression; interindividual variation; mRNA; miRNA; osteoblasts