Endothelial cell-secreted bone targeting exosomes promote angiogenesis coupling with osteogenesis via the PERK-ATF4-CRELD2 pathway

The role of endoplasmic reticulum (ER) stress in bone metabolism and the management of associated diseases has garnered significant interest. However, its role in regulating bone homeostasis and skeletal development remains largely unclear. Osteoblast development and bone formation are enhanced by a particular subtype of CD31hi endomucinhi (CD31hiEMCNhi) endothelium. However, it is still unclear how endothelial exosomes contribute to the production of CD31hiEMCNhi endothelium and bone formation. This research revealed that human umbilical vein endothelial cells (HUVECs)-exosomes (Exos) enhanced the formation of osteoblast and angiogenic effects in vitro. Furthermore, in mice treated with HUVECs-Exos, osteoblast production, and CD31hiEmcnhi vessels were significantly increased. The mechanism by which HUVECs-Exos CRELD2 improved angiogenesis coupling with osteogenesis involved triggering the PERK-ATF4-CRELD2 pathway's ER stress. As a result, HUVECs-Exos CRELD2 may be used as a potential bone metabolic disease nanodrug.