Abstract
Insufficient blood vessel supply is a primary limiting factor for regenerative approaches to large bone defect repair. Recombinant bone morphogenetic protein-2 (BMP-2) delivery induces robust bone formation and has been observed to enhance neovascularization, but whether the angiogenic effects of BMP-2 are due to direct endothelial cell stimulation or due to indirect paracrine signaling remain unclear. In this study, we evaluated the effects of BMP-2 delivery on vascularized bone regeneration and tested whether BMP-2 induces neovascularization directly or indirectly. We found that delivery of BMP-2 (5 μg) enhanced both bone formation and neovascularization in critically sized (8 mm) rat femoral bone defects; however, BMP-2 did not directly stimulate angiogenesis in vitro. In contrast, conditioned medium from both mesenchymal progenitor cells and osteoblasts induced endothelial cell migration in vitro, suggesting a paracrine mechanism of BMP-2 action. Consistent with this inference, codelivery of BMP-2 with endothelial colony forming cells to a heterotopic site, distant from the skeletal stem cell-rich bone marrow niche, induced ossification but had no effect on neovascularization. Taken together, these data suggest that paracrine activation of osteoprogenitor cells is an important contributor to neovascularization during BMP-2-mediated bone regeneration. Impact Statement In this study, we show that bone morphogenetic protein-2 (BMP-2) robustly induces neovascularization during tissue-engineered large bone defect regeneration, and we found that BMP-2 induced angiogenesis, in part, through paracrine signaling from osteoprogenitor cells.
Highlights
Critical-sized bone defects that do not heal without intervention have prolonged morbidity and are extremely costly.[1,2] Approximately 1.5 million bone grafting operations are performed annually in the United States.[3]
We evaluated the effects of BMP-2 delivery on neovascularization of large bone defects and whether BMP-2 directly induces endothelial cell activation or indirectly activates paracrine signaling from osteogenic cells
The objectives of this study were first to determine the extent to which BMP-2 enhances vascularized bone regeneration and second to test whether the neovascular response to BMP2 treatment is direct or indirect
Summary
Critical-sized bone defects that do not heal without intervention have prolonged morbidity and are extremely costly.[1,2] Approximately 1.5 million bone grafting operations are performed annually in the United States.[3] autologous bone is the ‘gold standard’ for bone grafting in segmental bone loss and intervertebral fusion, this treatment is limited by insufficient supply for large defects as well as substantial donor site pain and morbidity.[4]. Allografts are often required to bridge the defect, but with limitations including graft rejection, disease transmission, and lower rates of healing compared to autografts due to a failure to revascularize and remodel, leading to re-fracture.[5] Alternate regenerative strategies are needed, and tissue engineering has emerged as a promising alternative.
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