Extracellular Vesicles: The Common Language of Bone Formation and Pathological Calcification

Extracellular vesicles (EVs), including matrix vesicles and exosomes, are increasingly recognized as key mediators of intercellular communication and extracellular matrix remodeling. Originally described in physiological skeletal mineralization, EVs are now implicated in diverse pathological calcification processes, notably vascular calcification and bone metastasis. Despite occurring in distinct tissues, these conditions share common EV-driven mechanisms that regulate mineral deposition, cellular differentiation, and microenvironmental remodeling. This presentation aims to highlight the emerging concept that EVs constitute a conserved biological language governing both physiological bone formation and pathological ectopic calcification. We will discuss the molecular cargo, biogenesis, and functional roles of EVs across these seemingly disparate processes.During bone formation, osteoblast-derived matrix vesicles initiate hydroxyapatite nucleation through the coordinated activity of tissue-nonspecific alkaline phosphatase (TNAP), annexins, phosphatidylserine, and calcium/phosphate transporters. Remarkably, similar mechanisms operate in vascular calcification. Vascular smooth muscle cells undergoing osteogenic transdifferentiation release calcifying EVs enriched in phosphatidylserine, annexins, and pro-mineralization proteins. These vesicles serve as nucleation foci for calcium phosphate crystal formation within the vascular wall. Recent evidence further demonstrates that alterations in sphingolipid metabolism, inflammatory signaling, and EV cargo composition critically influence the calcification process.In the metastatic bone niche, tumor-derived EVs contribute to the establishment of a pre-metastatic microenvironment by modulating osteoblast, promoting extracellular matrix remodeling, and altering mineralization pathways. EV-mediated communication between cancer cells and bone-resident cells facilitates metastatic colonization and supports the vicious cycle of bone destruction and aberrant bone formation observed in skeletal metastases. EVs represent a unifying mechanistic platform linking physiological mineralization, vascular calcification, and bone metastasis. Understanding the shared molecular programs governing EV biogenesis, cargo loading, and mineralization competence may reveal novel biomarkers and therapeutic targets. Targeting EV-mediated communication could therefore offer innovative strategies to prevent pathological calcification while preserving physiological bone homeostasis.