Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease

Abstract

<b>Background</b>: As a hallmark driver of multiple myeloma (MM), MM bone disease (MBD) is unique in that it is characterized by severely impaired osteoblast activity resulting from blocked osteogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs). The mechanisms underlying this preferential blockade are incompletely understood. <b>Methods</b>: miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNA sequencing. MM-EVs impaired osteogenesis and exacerbated MBD were <i>in vitro</i> and <i>in vivo</i> validated by histochemical staining, qPCR and micro-CT. We additionally examined the correlation between CD138⁺ circulating EVs (cirEVs) count and bone lesion in <i>de novo</i> MM patients. <b>Results</b>: Here, by sequencing and bioinformatics analysis, we found that MM-EVs were enriched in various molecules negatively regulating osteogenesis. We experimentally verified that MM-EVs inhibited BM-MSC osteogenesis, induced elevated expression of miR-103a-3p inhibiting osteogenesis in BM-MSCs, and increased cell viability and interleukin-6 secretion in MM cells. In a mouse model, MM-EVs that were injected into the marrow space of the left tibia led to impaired osteogenesis and exacerbated MBD and MM progression. Furthermore, the levels of CD138⁺ cirEVs in the peripheral blood were positively correlated with the number of MM bone lesions in MM patients. <b>Conclusions</b>: These findings suggest that MM-EVs play a pivotal role in the development of severely impaired osteoblast activity, which represents a novel biomarker for the precise diagnosis of MBD and a compelling rationale for exploring MM-EVs as a therapeutic target.