Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling

Kimberly A. Jacobsen, Zainab S. Al-Aql, Chao Wan, Jennifer L. Fitch, Stephanie N. Stapleton, Zachary D. Mason, Robert M. Cole, Shawn R. Gilbert, Thomas Clemens, Elise F. Morgan, Thomas A. Einhorn, Louis C. Gerstenfeld

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)596-609
Number of pages14
JournalJournal of Bone and Mineral Research
Volume23
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

Distraction Osteogenesis
Osteogenesis
Antibodies
Chondrogenesis
Vascular Endothelial Growth Factor A
Ligands
Messenger RNA
Therapeutics
Tibia
Cartilage
Blood Vessels

Keywords

  • Angiogenesis
  • Bone morphogenetic protein
  • Distraction osteogenesis
  • Vascular endothelial growth factor
  • Vascular endothelial growth factor receptors

ASJC Scopus subject areas

  • Surgery

Cite this

Jacobsen, K. A., Al-Aql, Z. S., Wan, C., Fitch, J. L., Stapleton, S. N., Mason, Z. D., ... Gerstenfeld, L. C. (2008). Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. Journal of Bone and Mineral Research, 23(5), 596-609. https://doi.org/10.1359/jbmr.080103

Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. / Jacobsen, Kimberly A.; Al-Aql, Zainab S.; Wan, Chao; Fitch, Jennifer L.; Stapleton, Stephanie N.; Mason, Zachary D.; Cole, Robert M.; Gilbert, Shawn R.; Clemens, Thomas; Morgan, Elise F.; Einhorn, Thomas A.; Gerstenfeld, Louis C.

In: Journal of Bone and Mineral Research, Vol. 23, No. 5, 05.2008, p. 596-609.

Research output: Contribution to journalArticle

Jacobsen, KA, Al-Aql, ZS, Wan, C, Fitch, JL, Stapleton, SN, Mason, ZD, Cole, RM, Gilbert, SR, Clemens, T, Morgan, EF, Einhorn, TA & Gerstenfeld, LC 2008, 'Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling', Journal of Bone and Mineral Research, vol. 23, no. 5, pp. 596-609. https://doi.org/10.1359/jbmr.080103
Jacobsen, Kimberly A. ; Al-Aql, Zainab S. ; Wan, Chao ; Fitch, Jennifer L. ; Stapleton, Stephanie N. ; Mason, Zachary D. ; Cole, Robert M. ; Gilbert, Shawn R. ; Clemens, Thomas ; Morgan, Elise F. ; Einhorn, Thomas A. ; Gerstenfeld, Louis C. / Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. In: Journal of Bone and Mineral Research. 2008 ; Vol. 23, No. 5. pp. 596-609.
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abstract = "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.",
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T1 - Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling

AU - Jacobsen, Kimberly A.

AU - Al-Aql, Zainab S.

AU - Wan, Chao

AU - Fitch, Jennifer L.

AU - Stapleton, Stephanie N.

AU - Mason, Zachary D.

AU - Cole, Robert M.

AU - Gilbert, Shawn R.

AU - Clemens, Thomas

AU - Morgan, Elise F.

AU - Einhorn, Thomas A.

AU - Gerstenfeld, Louis C.

PY - 2008/5

Y1 - 2008/5

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Bone morphogenetic protein

KW - Distraction osteogenesis

KW - Vascular endothelial growth factor

KW - Vascular endothelial growth factor receptors

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