Multiple myeloma gammopathies

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

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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.

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Acknowledgements

This work was supported in part by NCI R01 CA181683-01A1 and R01 CA205954-01, Leukemia and Lymphoma Society and Multiple Myeloma Research Foundation. This work was also supported by the Danish Council for Independent Research, the Danish Cancer Society, Direktoer Ib Henriksens Foundation, the Lundbeck Foundation, the Niels Bohr Foundation, the Novo Nordisk Foundation, and the Dagmar Marshalls Foundation. ST was supported by a postdoctoral fellowship from the Uehara Memorial Foundation, Japan. We thank Ms. Catherine A. Sypher for technical assistance with animal experiments and Ms. Suzan Lazo for technical assistance with flow cytometric analysis.

Author contributions

ST, MBL, KZS, MRR, SK, and IMG conceived and designed the experiments. ST, MBL, and KZS performed in vitro studies. MR and DH collected clinical samples. ST, OZ, and YK performed in vivo studies. MBL, JP, and AP performed bioinformatics analysis. ST, MBL, SM, ST, KK, CAT, and MC analyzed the data. KN performed bone histomorphometric analysis. ST and MBL wrote the manuscript with input from AMR, RB, SK, and IMG.

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Correspondence to Sakari Kauppinen or Irene M. Ghobrial.

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Tsukamoto, S., Løvendorf, M.B., Park, J. et al. Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche. Leukemia 32, 1739–1750 (2018) doi:10.1038/s41375-018-0161-6

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