Axial shortening during distraction osteogenesis leads to enhanced bone formation in a rabbit model through the HIF-1α/vascular endothelial growth factor system

Abstract

Axial micromotion of bone fragments enhances callus formation during fracture repair or limb lengthening. To examine this, we used an axial-shortening model of the tibial callus in rabbits and performed histological analyses. After 10-mm lengthening of the left tibia with an external fixator, we shortened the callus by 2 mm. Radiographs and quantitative evaluation of corrected bone mineral density showed a significant increase in mineralization in the shortened callus (57.3 vs. 36.2%, p = 0.001). Histologically, greater osteoblast proliferation and more vigorous trabecular bone formation were noted in the shortened calluses than in the controls. Around the front of membranous bone formation in the shortened callus, there was a significant decrease in mean percentage area of vascular lumens (1.8 vs. 4.5%, p = 0.009), which seemed attributable to compressive force, and a significantly increased production of vascular endothelial growth factor (VEGF; 422.5 vs. 142.7 pg/mg protein, p = 0.007) and its receptors. There were also increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and proliferating cell nuclear antigen (PCNA)-positive cells. A marked increase of hypoxia inducible factor-1alpha (HIF-1alpha) expression in osteoblasts was also observed in this area. Thus, enhancement of membranous bone formation by static compression or axial dynamization may be at least partly attributable to HIF-1alpha-mediated VEGF induction following the local hypoxia caused by collapse of vascular lumens.