title: Soluble VEGFR1 reverses BMP2 inhibition of intramembranous ossification during healing of cortical bone defects.
abstract: BMP2 is widely used for promotion of bone repair and regeneration. However, bone formation induced by BMP2 is quite variable. Bone forming progenitor cells in different locations appear to respond to BMP2 in different ways, and repair outcomes can vary as a consequence of modulating effects by other factors. In this study, we have examined the effects of VEGF on BMP2-induced repair of a cortical bone defect, a 1 mm diameter drill hole, in the proximal tibia of mice. Treatment of the defect with either a bolus of PBS or soluble VEGFR1 (sVEGFR1), a decoy receptor for VEGF, had the same effects on bone formation via intramembranous ossification in the defect and cartilage formation and injured periosteum, during the healing process. In contrast, treatment with BMP2 inhibited intramembranous bone formation in the defect while it promoted cartilage and endochondral bone formation in the injured periosteum compared with mice treated with PBS or sVEGFR1. The inhibitory effect of BMP2 on bone formation was unlikely due to increased osteoclast activity and decreased invasion of blood vessels in the defect. Most importantly, co-delivery of BMP2 and sVEGFR1 reversed the inhibition of intramembranous bone formation by BMP2. Furthermore, the decreased accumulation of collagen and production of bone matrix proteins in the defect of groups with BMP2 treatment could also be prevented by co-delivery of BMP2 and sVEGFR1. Our data indicate that introducing a VEGF-binding protein, such as sVEGFR1, to reduce levels of extracellular VEGF, may enhance the effects of BMP2 on intramembranous bone formation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1461-1469, 2017.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Besschetnova
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000188:drug therapy; D006023:Glycoproteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055396:Bone Morphogenetic Protein 2; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: BMP2; VEGF; bone repair; cortical defect healing; soluble VEGFR1