MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells
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MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells. / Chen, Li; Holmstrøm, Kim; Qiu, Weimin; Ditzel, Nicholas; Shi, Kaikai; Hokland, Lea; Kassem, Moustapha.
I: Stem Cells, Bind 32, Nr. 4, 04.2014, s. 902-12.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - MicroRNA-34a inhibits osteoblast differentiation and in vivo bone formation of human stromal stem cells
AU - Chen, Li
AU - Holmstrøm, Kim
AU - Qiu, Weimin
AU - Ditzel, Nicholas
AU - Shi, Kaikai
AU - Hokland, Lea
AU - Kassem, Moustapha
N1 - © AlphaMed Press.
PY - 2014/4
Y1 - 2014/4
N2 - Osteoblast differentiation and bone formation (osteogenesis) are regulated by transcriptional and post-transcriptional mechanisms. Recently, microRNAs (miRNAs) were identified as novel key regulators of human stromal (skeletal, mesenchymal) stem cells (hMSC) differentiation. Here, we identified miRNA-34a (miR-34a) and its target protein networks as modulator of osteoblastic (OB) differentiation of hMSC. miRNA array profiling and further validation by quantitative RT-PCR revealed that miR-34a was upregulated during OB differentiation of hMSC, and in situ hybridization confirmed its OB expression in vivo. Overexpression of miR-34a inhibited early commitment and late OB differentiation of hMSC in vitro, whereas inhibition of miR-34a by anti-miR-34a enhanced these processes. Target prediction analysis and experimental validation confirmed Jagged1 (JAG1), a ligand for Notch 1, as a bona fide target of miR-34a. siRNA-mediated reduction of JAG1 expression inhibited OB differentiation. Moreover, a number of known cell cycle regulator and cell proliferation proteins, such as cyclin D1, cyclin-dependent kinase 4 and 6 (CDK4 and CDK6), E2F transcription factor three, and cell division cycle 25 homolog A were among miR-34a targets. Furthermore, in a preclinical model of in vivo bone formation, overexpression of miR-34a in hMSC reduced heterotopic bone formation by 60%, and conversely, in vivo bone formation was increased by 200% in miR-34a-deficient hMSC. miRNA-34a exhibited unique dual regulatory effects controlling both hMSC proliferation and OB differentiation. Tissue-specific inhibition of miR-34a might be a potential novel therapeutic strategy for enhancing in vivo bone formation.
AB - Osteoblast differentiation and bone formation (osteogenesis) are regulated by transcriptional and post-transcriptional mechanisms. Recently, microRNAs (miRNAs) were identified as novel key regulators of human stromal (skeletal, mesenchymal) stem cells (hMSC) differentiation. Here, we identified miRNA-34a (miR-34a) and its target protein networks as modulator of osteoblastic (OB) differentiation of hMSC. miRNA array profiling and further validation by quantitative RT-PCR revealed that miR-34a was upregulated during OB differentiation of hMSC, and in situ hybridization confirmed its OB expression in vivo. Overexpression of miR-34a inhibited early commitment and late OB differentiation of hMSC in vitro, whereas inhibition of miR-34a by anti-miR-34a enhanced these processes. Target prediction analysis and experimental validation confirmed Jagged1 (JAG1), a ligand for Notch 1, as a bona fide target of miR-34a. siRNA-mediated reduction of JAG1 expression inhibited OB differentiation. Moreover, a number of known cell cycle regulator and cell proliferation proteins, such as cyclin D1, cyclin-dependent kinase 4 and 6 (CDK4 and CDK6), E2F transcription factor three, and cell division cycle 25 homolog A were among miR-34a targets. Furthermore, in a preclinical model of in vivo bone formation, overexpression of miR-34a in hMSC reduced heterotopic bone formation by 60%, and conversely, in vivo bone formation was increased by 200% in miR-34a-deficient hMSC. miRNA-34a exhibited unique dual regulatory effects controlling both hMSC proliferation and OB differentiation. Tissue-specific inhibition of miR-34a might be a potential novel therapeutic strategy for enhancing in vivo bone formation.
KW - Calcium-Binding Proteins
KW - Cell Cycle Proteins
KW - Cell Differentiation
KW - Cell Proliferation
KW - Humans
KW - Intercellular Signaling Peptides and Proteins
KW - Membrane Proteins
KW - Mesenchymal Stromal Cells
KW - MicroRNAs
KW - Osteoblasts
KW - Osteogenesis
KW - Receptor, Notch1
U2 - 10.1002/stem.1615
DO - 10.1002/stem.1615
M3 - Journal article
C2 - 24307639
VL - 32
SP - 902
EP - 912
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 4
ER -
ID: 160161647