Extracellular Vesicles-Mediated Crosstalk in Bone: miR-150-5p as a Mechanosensitive Inhibitor of Osteoclastogenesis

Abstract Bone is a dynamic tissue that is constantly remodelling via a tightly controlled balance between formation and resorption. However, when osteoclast-mediated resorption exceeds formation, it can lead to net bone loss and the development of osteoporosis. Osteoclastogenesis is regulated by local environmental cues, including paracrine factors released by resident cell populations. Extracellular vesicles (EVs) have recently emerged as key mediators of paracrine communication, though their role in osteoclastogenesis remains underexplored. Therefore, this study investigated how resident mesenchymal-derived bone cells and their secreted EVs modulate osteoclastogenesis, and delineate the signalling factors mediating this anti-catabolic communication. We demonstrate that the secretome of mesenchymal-derived bone cells inhibit osteoclast differentiation to differing degrees depending on the stage of lineage commitment and on the mechanical environment, and demonstrate that this inhibition is mediated via the release of EVs. In addition, we identified the terminally differentiated osteocyte as the optimal parent cell for the production of anti-catabolic EVs and demonstrated the importance EV dosage. Finally, we show that mechanosensitive miR-150-5p is packaged within osteocyte-derived EVs and inhibits osteoclast differentiation. Taken together, this study identifies mechanically-activated osteocyte derived EVs and miR-150-5p as key regulators of osteoclastogenesis and novel molecular therapies for skeletal pathologies.