Figure 7.

MM cells secrete EVs containing UPR-related molecules (as Bip proteins) and misfolded proteins; once internalized inside pre-osteoclast cells, MM-EVs are likely addressed to the ER, where they could release their cargo. Misfolded proteins are bound by BiP proteins, both endogenous and exogenous, allowing the dimerization and autophosphorylation of IRE1α. Activated IRE1α mediates the splicing of XBP1 mRNA, the nuclear translocation of XBP1 protein and the activation of NFATc1 gene expression, a key regulator of OC differentiation.