MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

Tilde Eskildsen, Hanna Taipaleenmäki, Jan Stenvang, Basem M Abdallah, Nicholas Ditzel, Anne Yael Nossent, Mads Bak, Sakari Kauppinen, Moustapha Kassem

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3' UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.
OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind108
Udgave nummer15
Sider (fra-til)6139-44
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 2011

Fingeraftryk

MicroRNAs
Mesenchymal Stromal Cells
Osteoblasts
Osteogenesis
Luciferases
Alkaline Phosphatase
Cell Differentiation
Polymerase Chain Reaction

Citer dette

Eskildsen, Tilde ; Taipaleenmäki, Hanna ; Stenvang, Jan ; Abdallah, Basem M ; Ditzel, Nicholas ; Nossent, Anne Yael ; Bak, Mads ; Kauppinen, Sakari ; Kassem, Moustapha. / MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. I: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Bind 108, Nr. 15. s. 6139-44.
@article{3b8d28eac9224d849837ce6b39262074,
title = "MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo",
abstract = "Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85{\%}, and conversely, in vivo bone formation was enhanced by 60{\%} when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3' UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.",
author = "Tilde Eskildsen and Hanna Taipaleenm{\"a}ki and Jan Stenvang and Abdallah, {Basem M} and Nicholas Ditzel and Nossent, {Anne Yael} and Mads Bak and Sakari Kauppinen and Moustapha Kassem",
year = "2011",
doi = "10.1073/pnas.1016758108",
language = "English",
volume = "108",
pages = "6139--44",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "15",

}

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo. / Eskildsen, Tilde; Taipaleenmäki, Hanna; Stenvang, Jan; Abdallah, Basem M; Ditzel, Nicholas; Nossent, Anne Yael; Bak, Mads; Kauppinen, Sakari; Kassem, Moustapha.

I: Proceedings of the National Academy of Sciences of the United States of America, Bind 108, Nr. 15, 2011, s. 6139-44.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

AU - Eskildsen, Tilde

AU - Taipaleenmäki, Hanna

AU - Stenvang, Jan

AU - Abdallah, Basem M

AU - Ditzel, Nicholas

AU - Nossent, Anne Yael

AU - Bak, Mads

AU - Kauppinen, Sakari

AU - Kassem, Moustapha

PY - 2011

Y1 - 2011

N2 - Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3' UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.

AB - Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3' UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.

U2 - 10.1073/pnas.1016758108

DO - 10.1073/pnas.1016758108

M3 - Journal article

C2 - 21444814

VL - 108

SP - 6139

EP - 6144

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 15

ER -