Fracture repair by IOX2: Regulation of the hypoxia inducible factor-1α signaling pathway and BMSCs

Abstract

The treatment of fracture delayed union and nonunion has become a challenging problem. Hypoxia inducible factor-1α (HIF-1α) is reported to be a key factor in fracture healing, and is degraded by hydroxylation of prolyl hydroxylase (PHDs) under normal oxygen. Small molecules could inhibit the activity of PHDs, stabilize HIF-1α protein, regulate the expression of downstream target genes of HIF-1α, and make the body adapt to hypoxia. The migration and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is the most promising candidate for the treatment of fracture nonunion. Here we reported that IOX2, an HIF-1α PHD inhibitor, markedly improved the proliferation and migration of BMSCs by upregulating intracellular Ca2+ and concomitant decreasing reactive oxygen species (ROS) in vitro, and facilitated the repair of bone fracture by increasing the number of BMSCs and cartilage formation in vivo. No significant influence of IOX2 on the proliferation and migration of BMSCs after silencing of the HIF-1α. Together, our findings indicated that IOX2 promoted the proliferation and migration of BMSCs via the HIF-1α pathway and further accelerated fracture healing. These results provide a deeper understanding of the mechanism by which HIF promotes fracture healing.