Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration

Abstract

The hypoxia-inducible factor-1alpha (HIF-1alpha) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1alpha pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1alpha activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1alpha in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1alpha pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.

Evaluating effects of deferoxamine in a rat tibia critical bone defect model

“…It has been observed to induce upregulation of HIF (Hypoxia Inducible Factor) which in its turn upregulates VEGF (vascular endothelial growth factor). 6 VEGF has been found to play an important role in the fracture healing response as well as in recruiting new vasculature. Recently, it has been demonstrated in an unimpaired, closed fracture healing model that injection of DFO at the injury can increase vascularity and bone volume at the fracture site.…”

Small Molecule Derived From Carboxyethylpyrrole Protein Adducts Promotes Angiogenesis in a Mouse Model of Peripheral Arterial Disease

“…Desferoxamine, one of the most established iron chelators, activates HIF‐1 (hypoxia inducible factor 1) and induces high‐level expression of VEGF and erythropoietin mRNA 27, 28. Desferoxamine was also demonstrated to increase tubelike structure formation on Matrigel with human umbilical vein ECs 29. In addition, desferoxamine enhanced endothelial sprouting and vessel formation both in vitro and in vivo 29.…”

“…Desferoxamine was also demonstrated to increase tubelike structure formation on Matrigel with human umbilical vein ECs 29. In addition, desferoxamine enhanced endothelial sprouting and vessel formation both in vitro and in vivo 29. However, because iron is also a cofactor for oxidative phosphorylation and arachidonic acid signaling, a limitation of desferoxamine's translational potential is its off‐target effects 30.…”

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

“…We and others have shown that periosteum-derived cells are likely contributing to this reaction, as they are able to mount a strong pro-angiogenic and osteogenic response following exposure to hypoxia in vitro (Ichijima et al, 2012;van Gastel et al, 2012). In addition, activation of the HIF pathway also contributes to improved bone regeneration, as shown in a model of distraction osteogenesis, where enhanced hypoxia signalling in osteoblasts leads to better vascularization and bone regeneration in a VEGFdependent manner (Wan et al, 2008). Moreover, compounds that induce hypoxia signalling are reported to promote fracture healing in rodents (Shen et al, 2009;Wan et al, 2008).…”

“…In addition, activation of the HIF pathway also contributes to improved bone regeneration, as shown in a model of distraction osteogenesis, where enhanced hypoxia signalling in osteoblasts leads to better vascularization and bone regeneration in a VEGFdependent manner (Wan et al, 2008). Moreover, compounds that induce hypoxia signalling are reported to promote fracture healing in rodents (Shen et al, 2009;Wan et al, 2008).…”