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dc.contributor.authorCamp-Dotlic, E.-
dc.contributor.authorPribadi, C.-
dc.contributor.authorAnderson, P.-
dc.contributor.authorZannettino, A.-
dc.contributor.authorGronthos, S.-
dc.identifier.citationStem Cells and Development, 2018; 27(23):1621-1633-
dc.description.abstractKey transcription factors, which activate or repress master gene regulators and signalling pathways, tightly regulate self-renewal and cell lineage differentiation of bone marrow stromal cells (BMSC). Among these factors is the basic helix-loop-helix (bHLH) transcription factor Twist-related protein 1 (TWIST-1), which is important in BMSC self-renewal, life span and differentiation. Another layer of gene regulation comes from MicroRNAs (miRNAs). MiRNAs are short non-coding RNAs that interfere with translation of specific target mRNAs and thereby regulate diverse biological processes including BMSC lineage commitment. However, little is known of how TWIST-1 regulated miRNAs control osteogenic commitment, and influence the fate of bone precursor cells. In this study, we have discovered a novel TWIST-1 regulated miRNA, miR-376c-3p. Reduced miR-376c-3p expression by a miR-376c-3p inhibitor or due to TWIST-1 haploinsufficiency promotes alkaline phosphatase activity, mineral deposition and expression of osteoblast-associated genes in BMSC and calvarial cells. Conversely, over-expression of miR-376c-3p using a miR-376c-3p mimic inhibited BMSC proliferation and the osteogenic potential of BMSC and TWIST-1 haploinsufficient calvarial cells. This was demonstrated by a decrease in Insulin Growth factor 1 receptor (IGF1R) levels, Akt signalling, alkaline phosphatase activity, mineral deposition and expression of osteoblast-associated genes. Thus, miR-376c-3p reduces IGF1R/Akt signalling in BMSC and is one mechanism by which osteogenesis may be inhibited. Overall, we have identified miR-376c-3p as a TWIST-1 regulated miRNA, which plays an important role in the osteogenesis of bone precursor cells and can mediate TWIST-1 inhibition of osteogenesis. Furthermore, over-expression of miRNA-376c-3p in TWIST-1 haploinsufficient calvarial cells can decrease the aberrant osteogenesis of these cells, which contributes to increased calvaria bone volume and premature fusion of the coronal sutures.-
dc.description.statementofresponsibilityEsther Camp, Clara Pribadi, Peter J. Anderson, Andrew C.W. Zannettino and Stan Gronthos-
dc.publisherMary Ann Liebert-
dc.rights© Mary Ann Liebert, Inc.-
dc.subjectMesenchymal stem cells; TWIST-1; miR-376c-3p; insulin growth factor 1 receptor; osteogenesis-
dc.titlemiRNA-376c-3p mediates TWIST-1 inhibition of BMSC osteogenesis and can reduce aberrant bone formation of TWIST-1 haploinsufficient calvarial cells-
dc.typeJournal article-
dc.identifier.orcidPribadi, C. [0000-0001-9634-2678]-
dc.identifier.orcidAnderson, P. [0000-0002-3730-4652]-
dc.identifier.orcidZannettino, A. [0000-0002-6646-6167]-
dc.identifier.orcidGronthos, S. [0000-0002-6225-3084]-
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