HIF-1α promotes osteogenic regeneration of titanium implants by coupling angiogenesis and osteogenesis via HIF-1α/VEGF/AKT/mTOR signaling pathway

Abstract

Abstract Background: Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) could directly increase cancellous bone formation and was playing an essential role in bone modeling and remodeling. However, whether an increase of HIF-1α in ADSCs promoted osteogenic differentiation and bone formation was not known. Results: In this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression cDNA were established to investigate the proliferation, migration, adhesion, and osteogenic capacity in ADSCs, and angiogenic ability in HUVEC. Overexpression of HIF-1α could promote cell proliferation, migration, adhesive and osteogenic capacity of ADSCs and angiogenic ability of HUVEC. Western blotting showed that the protein levels of osteogenesis-related factors were upregulated when overexpression of HIF-1α. Furthermore, the influence of up-regulating HIF-1α in ADSCs sheets on osseointegration had evaluated using the SD rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The over-expression of HIF-1α in ADSCs enhanced osteogenic differentiation and osseointegration around implants. Whereas transfecting HIF-1α-silenced ADSCs attenuated the osteogenic and angiogenic capacity. Finally, to explore the mechanism underlying HIF-1α promoted osteogenesis and angiogenesis, Western blotting was measured to analyze the VEGF/AKT/mTOR signaling pathway. Conclusions: These data first demonstrated that up-regulation of HIF-1α in ADSCs significantly improved the osteogenic capacity and peri-implant bone formation via VEGF/AKT/mTOR signaling pathway. Our findings revealed that HIF-1α exerts a critical effect on promoting osseointegration by improving osteogenesis and angiogenesis via VEGF/AKT/mTOR signaling pathway, and hence offered the considerable therapeutic potential for modifying stem cells to enhance osseointegration.