Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche

Shokichi Tsukamoto; Marianne B Løvendorf; Jihye Park; Karma Z Salem; Michaela R Reagan; Salomon Manier; Oksana Zavidij; Mahshid Rahmat; Daisy Huynh; Satoshi Takagi; Yawara Kawano; Katsutoshi Kokubun; Charlotte Albæk Thrue; Kenichi Nagano; Andreas Petri; Aldo M Roccaro; Marzia Capelletti; Roland Baron; Sakari Kauppinen; Irene M Ghobrial

doi:10.1038/s41375-018-0161-6

Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche

Shokichi Tsukamoto, Marianne B Løvendorf, Jihye Park, Karma Z Salem, Michaela R Reagan, Salomon Manier, Oksana Zavidij, Mahshid Rahmat, Daisy Huynh, Satoshi Takagi, Yawara Kawano, Katsutoshi Kokubun, Charlotte Albæk Thrue, Kenichi Nagano, Andreas Petri, Aldo M Roccaro, Marzia Capelletti, Roland Baron, Sakari Kauppinen, Irene M Ghobrial

Research output: Contribution to journal › Journal article › Research › peer-review

33 Citations (Scopus)

Abstract

Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

Original language	English
Journal	Leukemia
Volume	32
Issue number	8
Pages (from-to)	1739-1750
Number of pages	12
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-018-0161-6
Publication status	Published - 2018

Access to Document

10.1038/s41375-018-0161-6

AUB Link

Search for the material in Aalborg University Library's search engine

Cite this

Tsukamoto, S., Løvendorf, M. B., Park, J., Salem, K. Z., Reagan, M. R., Manier, S., Zavidij, O., Rahmat, M., Huynh, D., Takagi, S., Kawano, Y., Kokubun, K., Thrue, C. A., Nagano, K., Petri, A., Roccaro, A. M., Capelletti, M., Baron, R., Kauppinen, S., & Ghobrial, I. M. (2018). Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche. Leukemia, 32(8), 1739-1750. https://doi.org/10.1038/s41375-018-0161-6

@article{16faa21035404a78a63ffaacb3c6806c,

title = "Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche",

abstract = "Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.",

author = "Shokichi Tsukamoto and L{\o}vendorf, {Marianne B} and Jihye Park and Salem, {Karma Z} and Reagan, {Michaela R} and Salomon Manier and Oksana Zavidij and Mahshid Rahmat and Daisy Huynh and Satoshi Takagi and Yawara Kawano and Katsutoshi Kokubun and Thrue, {Charlotte Alb{\ae}k} and Kenichi Nagano and Andreas Petri and Roccaro, {Aldo M} and Marzia Capelletti and Roland Baron and Sakari Kauppinen and Ghobrial, {Irene M}",

year = "2018",

doi = "10.1038/s41375-018-0161-6",

language = "English",

volume = "32",

pages = "1739--1750",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

number = "8",

}

Tsukamoto, S, Løvendorf, MB, Park, J, Salem, KZ, Reagan, MR, Manier, S, Zavidij, O, Rahmat, M, Huynh, D, Takagi, S, Kawano, Y, Kokubun, K, Thrue, CA, Nagano, K, Petri, A, Roccaro, AM, Capelletti, M, Baron, R, Kauppinen, S & Ghobrial, IM 2018, 'Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche', Leukemia, vol. 32, no. 8, pp. 1739-1750. https://doi.org/10.1038/s41375-018-0161-6

TY - JOUR

T1 - Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche

AU - Tsukamoto, Shokichi

AU - Løvendorf, Marianne B

AU - Park, Jihye

AU - Salem, Karma Z

AU - Reagan, Michaela R

AU - Manier, Salomon

AU - Zavidij, Oksana

AU - Rahmat, Mahshid

AU - Huynh, Daisy

AU - Takagi, Satoshi

AU - Kawano, Yawara

AU - Kokubun, Katsutoshi

AU - Thrue, Charlotte Albæk

AU - Nagano, Kenichi

AU - Petri, Andreas

AU - Roccaro, Aldo M

AU - Capelletti, Marzia

AU - Baron, Roland

AU - Kauppinen, Sakari

AU - Ghobrial, Irene M

PY - 2018

Y1 - 2018

N2 - Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

AB - Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

UR - http://www.scopus.com/inward/record.url?scp=85048718314&partnerID=8YFLogxK

U2 - 10.1038/s41375-018-0161-6

DO - 10.1038/s41375-018-0161-6

M3 - Journal article

C2 - 29925904

SN - 0887-6924

VL - 32

SP - 1739

EP - 1750

JO - Leukemia

JF - Leukemia

IS - 8

ER -

Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche

Abstract

Access to Document

AUB Link

Other files and links

Fingerprint

Cite this