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

Zhang, Liming, Qian Lei, Hongxiang Wang, Cuiwei Xu, Teng Liu, Fancong Kong, Cui Yang et al. "Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease." Theranostics 9, no. 1 (2019): 196.

Abstract
Background: 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.
Methods: miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNA
sequencing. MM-EVs impaired osteogenesis and exacerbated MBD were in vitro and in vivo validated by
histochemical 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 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.
Conclusions: 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.

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