VEGF Improves, Whereas sFlt1 Inhibits, BMP2-Induced Bone Formation and Bone Healing Through Modulation of Angiogenesis

Abstract

We studied the interaction between VEGF and BMP2 during bone formation and bone healing. Results indicate that VEGF antagonist inhibited BMP2-elicited bone formation, whereas the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing through modulation of angiogenesis.Introduction: Angiogenesis is closely associated with bone formation during normal bone development and is important for the bone formation elicited by BMP4. However, it remains unknown whether vascular endothelial growth factor (VEGF) also interacts with other BMPs, especially BMP2, in bone formation and bone healing. Materials and Methods: For this study, mouse muscle-derived stem cells were transduced to express BMP2, VEGF, or VEGF antagonist (sFlt1). We studied the angiogenic process during endochondral bone formation elicited by BMP2, a prototypical osteogenic BMP. Using radiographic and histologic analyses, we also evaluated the interaction between VEGF and BMP2 during bone formation and bone healing. Results: Our results indicate that BMP2-elicited bone formation comprises two phases of angiogenesis, with an early phase occurring before the appearance of hypertrophic cartilage, followed by a late phase coupled with the appearance of hypertrophic cartilage. Our finding that the administration of sFlt1, a specific antagonist of VEGF, significantly inhibited BMP2-induced bone formation and the associated angiogenesis indicates that endogenous VEGF activity is important for bone formation. Furthermore, we found that the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing by improving angiogenesis, which in turn led to accelerated cartilage resorption and enhanced mineralized bone formation. Our findings also indicate that the ratio between VEGF and BMP2 influences their synergistic interaction, with a higher proportion of VEGF leading to decreased synergism. Our study also revealed unique VEGF-BMP2 interactions that differ from the VEGF-BMP4 interactions that we have described previously. Conclusions: This study, along with previously published work, shows that VEGF interacts synergistically with both BMP4 and BMP2 but elicits substantially different effects with these two BMPs.

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

“…This interactive biology is difficult to reproduce in vitro. The hallmark of this process is BMP activity; it is known and accepted that BMP-2 is the prototypical molecule for osteogenesis [50]. Terminal osteogenic differentiation is promoted by rhBMP-2; thus, abrogating BMP-induced differentiation has a robust biological basis for HO prophylaxis [32,42].…”

Emerging Ideas: Treatment of Precollapse Osteonecrosis Using Stem Cells and Growth Factors

“…Combined use of VEGF and BMP-2 [19,24,34,35,37,40] and BMP-4 [20,25,36] showed synergistic effects in osteogenesis. It has been shown that combined use of VEGF with one of the most potent BMPs, BMP-6 [23,26], enhances osteogenesis and angiogenesis of mouse bone marrow stem cells in vitro and in vivo [8], however, the effectiveness of this therapy for ON has not been determined.…”

“…Direct VEGF administration can improve blood flow and neovascularization in necrotic bone [38]. In addition to its effects on angiogenesis, VEGF plays an important role in bone growth and repair by interacting with other growth factors [35,36]. However, overexpression of VEGF actually can adversely affect osteogenesis and decrease bone formation [25,[34][35][36][37].…”

“…In addition to its effects on angiogenesis, VEGF plays an important role in bone growth and repair by interacting with other growth factors [35,36]. However, overexpression of VEGF actually can adversely affect osteogenesis and decrease bone formation [25,[34][35][36][37]. In our in vitro study, the optimal ratio of VEGF and BMP-6 will be determined so that the undesired effects of VEGF can be avoided in the in vivo study.…”

“…Stem cell-mediated bone regeneration augmented with combined use of VEGF and BMPs has been reported but only for BMP-2 [19,24,34,35,37,40] and BMP-4 [20,25,36]. It has been shown that VEGF enhances BMP-6-induced osteogenesis of mouse stem cells in vitro and in vivo, however, the effectiveness of this therapy for ON has not been determined [8].…”