Therapeutic effects of Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha}) on bone formation around implants in diabetic mice

Patients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1 on bone formation around implants by applying HIF-1 to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1 and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1 gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1 gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1 target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1 were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1 via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.