The authors state that they have no conflicts of interest.
Bone Formation During Distraction Osteogenesis Is Dependent on Both VEGFR1 and VEGFR2 Signaling†
Article first published online: 4 FEB 2008
Copyright © 2008 ASBMR
Journal of Bone and Mineral Research
Volume 23, Issue 5, pages 596–609, May 2008
How to Cite
Jacobsen, K. A., Al-Aql, Z. S., Wan, C., Fitch, J. L., Stapleton, S. N., Mason, Z. D., Cole, R. M., Gilbert, S. R., Clemens, T. L., Morgan, E. F., Einhorn, T. A. and Gerstenfeld, L. C. (2008), Bone Formation During Distraction Osteogenesis Is Dependent on Both VEGFR1 and VEGFR2 Signaling. J Bone Miner Res, 23: 596–609. doi: 10.1359/jbmr.080103
- Issue published online: 4 DEC 2009
- Article first published online: 4 FEB 2008
- Manuscript Accepted: 28 JAN 2008
- Manuscript Revised: 2 JAN 2008
- Manuscript Received: 6 JUN 2007
- distraction osteogenesis;
- vascular endothelial growth factor;
- vascular endothelial growth factor receptors;
- bone morphogenetic protein
Introduction: Distraction osteogenesis (DO) is characterized by the induction of highly vascularized new bone formation through an intramembranous process largely devoid of the formation of cartilage.
Materials and Methods: To test the hypothesis that DO is strictly dependent on vascualrization, we inhibited vascular endothelial growth factor (VEGF) activity by antibody blockade of both receptors VEGFR1 (Flt-1) and VEGFR2 (Flk-1) or only VEGFR2 (Flk-1) in a previously developed murine tibia DO model. During normal DO, VEGFR1 (Flt-1), VEGFR2 (Flk-1), VEGFR3 (Flt4) and all four VEGF ligand (A, B, C, and D) mRNAs are induced.
Results: The expression of mRNA for the receptors generally paralleled those of the ligands during the period of active distraction. Bone formation, as assessed by μCT, showed a significant decrease with the double antibody treatment and a smaller decrease with single antibody treatment. Vessel volume, number, and connectivity showed progressive and significant inhibition in all of these of parameters between the single and double antibody blockade. Molecular analysis showed significant inhibition in skeletal cell development with the single and double antibody blockade of both VEGFR1 and 2. Interestingly, the single antibody treatment led to selective early development of chondrogenesis, whereas the double antibody treatment led to a failure of both osteogenesis and chondrogenesis.
Conclusions: Both VEGFR1 and VEGFR2 are functionally essential in blood vessel and bone formation during DO and are needed to promote osteogenic over chondrogenic lineage progression.