Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

Abstract

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

Exosomes mediate intercellular transfer of non–autonomous tolerance to proteasome inhibitors in mixed‐lineage leukemia

“…We also found that the development of resistance conferred by exosomes could be inhibited by GW4869, possibly due to the blockade of exosome secretion by donor cells. GW4869 has already been used in vivo to inhibit exosome secretion in different disease models, and combination treatment with bortezomib led to a significant effect on tumor load …”

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

“…They revealed that DKK‐1 transfer resulted in a decrease in Collagen 1A1, Osterix, and Runx2 in OBs. Of note, they demonstrated that exosomes could mediate osteolysis in a similar pattern as the MM cells . Inhibition of the secretion of exosomes by the sphingomyelinase inhibitor GW4869 enhanced cortical bone volume and increased the sensitization of MM cells to bortezomib, resulting in a significant antitumor response when bortezomib and GW4869 were combined .…”

“…116 Overall, their findings showed that a crucial role for exosomes in the BM microenvironment and proposed a new therapeutic target for anti-MM therapy. 116 MiRNAs are important cargos that could be transferred by exosomes. It has been found that miR-340 transfection into BM-derived exosomes restores antiangiogenic features, which suggests that the replacement of exosomal miRNAs could have therapeutic benefits.…”

“…Because exosomes play such a prominent role in the MM microenvironment, they could represent mentioned targets. 115 In an in vivo investigation, by utilizing the 5TGM1 murine model, the impact of MM exosomes on various aspects of osteolysis was evaluated by Faict et al 116 Exosomes, in addition to enhance OCs activity, were also found to inhibit OBs functionality and differentiation in vitro. 116,117 They revealed that DKK-1 transfer resulted in a decrease in Collagen 1A1, Osterix, and Runx2 in OBs.…”

“…116 Inhibition of the secretion of exosomes by the sphingomyelinase inhibitor GW4869 enhanced cortical bone volume and increased the sensitization of MM cells to bortezomib, resulting in a significant antitumor response when bortezomib and GW4869 were combined. 116 Overall, their findings showed that a crucial role for exosomes in the BM microenvironment and proposed a new therapeutic target for anti-MM therapy. 116 MiRNAs are important cargos that could be transferred by exosomes.…”