Superior Angiogenic Potential of GDF-5 and GDF-5V453/V456 Compared with BMP-2 in a Rabbit Long-Bone Defect Model

Abstract

The clinical application of bone morphogenetic proteins such as BMP-2 and GDF-5 (growth and differentiation factor-5) may improve the outcome of bone defect repair. In addition to the osteoinductivity of BMPs, their angiogenic potential is important as an adequate blood supply is a prerequisite for bone-healing. We used a rabbit long-bone defect model to investigate whether angiogenicity and osteogenicity were correlated features of a BMP molecule by comparing the induction of blood vessel and bone formation by BMP-2, GDF-5, and a previously created swap mutant GDF-5V453/V456 (BB-1) with elevated BMP receptor-IA binding. Microcomputed tomography and immunohistochemistry were used to assess early bone formation and neovascularization in 15-mm (critical-sized) rabbit radius defects treated with a growth factor-loaded collagen carrier. Blood vessel volume and surface area on days 7 and 14 after surgery were significantly greater in defects treated with GDF-5 and with BB-1 compared with controls (p < 0.05); BMP-2 enhanced vascularization on day 14 (p < 0.05). Cumulative data including both time points reflected increased vessel volume, intersection surface area, and number of vessels after treatment with GDF-5 and BB-1 compared with BMP-2 (p < 0.05), corresponding to the histology results. Each of the growth factors resulted in enhanced bone formation compared with controls on day 14 (p < 0.01), with BB-1 resulting in significantly more bone compared with GDF-5 as indicated by bone volume and surface area (p = 0.006). Both GDF-5 and BB-1 had high angiogenicity, and BB-1 outperformed GDF-5 with respect to osteogenicity. Strong induction of bone formation by BMP-2 and BB-1 was thus associated with BMP receptor-IA-dependent signaling, whereas the vascularization outcome was not. Although both BMP-2 and the GDF-5 variant BB-1 are good inducers of bone formation, BB-1 is especially promising for long-bone healing if high angiogenicity is desired along with high osteogenicity to promote recreation of optimal bone architecture.