Aging Impairs Implant Osseointegration Through a Novel Reactive Oxygen Species-Hypoxia-Inducible Factor 1α/p53 Axis

Enhancing bone-vessel coupling to form high-quality vascular-rich peri-implant bone is crucial for improving implant prognosis in elder patients. Notably, hypoxia-inducible factor 1α (HIF1α) is known to promote osteogenesis-angiogenesis coupling; however, this effect remains to be investigated in aged bone owing to the dual effect of HIF1α in different aged organs. In this study, HIF1α inhibitor or activator was applied to aged mice and their bone mesenchymal stem cells (BMSCs) to investigate the effects and inner mechanism of HIF1α on the peri-implant osteogenesis and angiogenesis in senescent status. Cell senescence, along with osteogenic and angiogenic abilities of aged BMSCs, was detected, respectively. Meanwhile, a femur implant implantation model was constructed on aged mice, and the bone-vessel coupling of peri-implant bone was observed. Mandibular bone morphology was also detected to further provide evidence for clinical oral implantation. Furthermore, p53 expression was examined <i>in vivo</i> and <i>in vitro</i> following HIF1α intervention. A reactive oxygen species (ROS) scavenger was also adopted to further investigate the roles of ROS in the HIF1α-p53 axis. Results showed that the suppression of HIF1α alleviated senescence and osteogenesis-angiogenesis coupling of aged BMSCs, while its activation aggravated these effects. The mandible phenotype and bone-vessel coupling in aged peri-implant bone also changed accordingly upon regulation of HIF1α. Mechanistically, p53 changed in the same direction as HIF1α <i>in vivo</i> and <i>in vitro</i>. Moreover, the ROS scavenger reversed the HIF1α-p53 relationship and weakened the effect of HIF1α inhibitor on peri-implant bone improvement. In conclusion, in aged mice, highly expressed HIF1α impaired peri-implant bone-vessel coupling and implant osseointegration through p53, and accumulated ROS was a prerequisite for HIF1α to positively regulate p53. These findings provide new insights into the role of HIF1α and the ROS-HIF1α/p53 signaling axis, offering potential therapeutic targets to improve implant outcomes in elderly patients.