Angiogenesis is required for stress fracture healing in rats

Ryan E. Tomlinson, Jennifer A. McKenzie, Anne H. Schmieder, Gregory R. Wohl, Gregory M. Lanza, Matthew J. Silva

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Although angiogenesis and osteogenesis are critically linked, the importance of angiogenesis for stress fracture healing is unknown. In this study, mechanical loading was used to create a non-displaced stress fracture in the adult rat forelimb. Fumagillin, an anti-angiogenic agent, was used as the water soluble analogue TNP-470 (25mg/kg) as well as incorporated into lipid-encapsulated αvβ3 integrin targeted nanoparticles (0.25mg/kg). In the first experiment, TNP-470 was administered daily for 5days following mechanical loading, and changes in gene expression, vascularity, and woven bone formation were quantified. Although no changes in vascularity were detected 3days after loading, treatment-related downregulation of angiogenic (Pecam1) and osteogenic (Bsp, Osx) genes was observed at this early time point. On day 7, microCT imaging of loaded limbs revealed diminished woven bone formation in treated limbs compared to vehicle treated limbs. In the second experiment, αvβ3 integrin targeted fumagillin nanoparticles were administered as before, albeit with a 100-fold lower dose, and changes in vascularity and woven bone formation were determined. There were no treatment-related changes in vessel count or volume 3days after loading, although fewer angiogenic (CD105 positive) blood vessels were present in treated limbs compared to vehicle treated limbs. This result manifested on day 7 as a reduction in total vascularity, as measured by histology (vessel count) and microCT (vessel volume). Similar to the first experiment, treated limbs had diminished woven bone formation on day 7 compared to vehicle treated limbs. These results indicate that angiogenesis is required for stress fracture healing, and may have implications for inducing rapid repair of stress fractures.

Original languageEnglish
Pages (from-to)212-219
Number of pages8
JournalBone
Volume52
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Angiogenesis
  • Fumagillin
  • Mechanical loading
  • Stress fracture
  • TNP-470
  • Woven bone formation

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