GSE111651
Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche
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 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. Overall design: RNA sequencing of endosteal osteoblastic lineage cells (OBCs) from 4 C57BL/KaLwRij (KaLwRij) mice treated with anti-miR-138 LNA-modified antisense oligonucleotide and 4 KaLwRij mice treated with scramble control and RNA sequencing of primary human BM–derived MSCs obtained from normal healthy donors (ND-MSCs) co-cultured with myeloma cells (OPM2) and treated with anti-miR-138 LNA-modified antisense oligonucleotide (N=3) or scramble control (N=3)