Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche.
Document Type
Article
Publication Date
8-1-2018
Institution/Department
Maine Medical Center Research Institute
Journal Title
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
MeSH Headings
Animals, Biomarkers, Tumor, Bone Marrow, Case-Control Studies, Cell Differentiation, Cells, Cultured, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Mice, SCID, MicroRNAs, Multiple Myeloma, Osteoblasts, Osteogenesis, Prognosis
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.
ISSN
1476-5551
First Page
1739
Last Page
1750
Recommended Citation
Tsukamoto, Shokichi; Løvendorf, Marianne B; Park, Jihye; Salem, Karma Z; Reagan, Michaela R; Manier, Salomon; Zavidij, Oksana; Rahmat, Mahshid; Huynh, Daisy; Takagi, Satoshi; Kawano, Yawara; Kokubun, Katsutoshi; Thrue, Charlotte Albæk; Nagano, Kenichi; Petri, Andreas; Roccaro, Aldo M; Capelletti, Marzia; Baron, Roland; Kauppinen, Sakari; and Ghobrial, Irene M, "Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche." (2018). Maine Medical Center. 1603.
https://knowledgeconnection.mainehealth.org/mmc/1603
