Copper doped bioactive glass promotes matrix vesicles-mediated biomineralization via osteoblast mitophagy and mitochondrial dynamics during bone regeneration

Bone defect repair remains a great challenge in the field of orthopedics. Human body essential trace element such as copper is essential for bone regeneration, but how to use it in bone defects and the underlying its mechanisms of promoting bone formation need to be further explored. In this study, by doping copper into mesoporous bioactive glass nanoparticles (Cu-MBGNs), we unveil a previously unidentified role of copper in facilitating osteoblast mitophagy and mitochondrial dynamics, which enhance amorphous calcium phosphate (ACP) release and subsequent biomineralization, ultimately accelerating the process of bone regeneration. Specifically, by constructing conditional knockout mice lacking the autophagy gene Atg5 in osteogenic lineage cells, we first confirmed the role of Cu-MBGNs-promoted bone formation via mediating osteoblast autophagy pathway. Then, the in vitro studies revealed that Cu-MBGNs strengthened mitophagy by inducing ROS production and recruiting PINK1/Parkin, thereby facilitating the efficient release of ACP from mitochondria into matrix vesicles for biomineralization during bone regeneration. Moreover, we found that Cu-MBGNs promoted mitochondrion fission via activating dynamin related protein 1 (Drp1) to reinforce mitophagy pathway. Together, this study highlights the potential of Cu-MBGNs-mediated mitophagy and biomineralization for augmenting bone regeneration, offering a promising avenue for the development of advanced bioactive materials in orthopedic applications.