LAUSR

Background As a hallmark driver of multiple myeloma (MM), MM bone disease (MBD) is unique in thatit is characterized by severely impaired osteoblast activity resulting from blocked osteogenesis in bonemarrow-derived mesenchymal stem cells (BM-MSCs). The mechanisms underlying this preferentialblockade are incompletely understood. Methods miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNAsequencing. MM-EVs impaired osteogenesis and exacerbated MBD were in vitro and in vivo validated byhistochemical staining, qPCR and micro-CT. We additionally examined the correlation between CD138+circulating EVs (cirEVs) count and bone lesion in de novo MM patients. Results Here, by sequencing and bioinformatics analysis, we found that MM-EVs were enriched invarious molecules negatively regulating osteogenesis. We experimentally verified that MM-EVs inhibitedBM-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 wereinjected into the marrow space of the left tibia led to impaired osteogenesis and exacerbated MBD andMM progression. Furthermore, the levels of CD138+ cirEVs in the peripheral blood were positivelycorrelated with the number of MM bone lesions in MM patients. Conclusions These findings suggest that MM-EVs play a pivotal role in the development of severelyimpaired osteoblast activity, which represents a novel biomarker for the precise diagnosis of MBD and acompelling rationale for exploring MM-EVs as a therapeutic target.