EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair

Authors

  • Agnieszka Arthur,

    1. Mesenchymal Stem Cell Group, Department of Haematology, SA Pathology Adelaide and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Romana A Panagopoulos,

    1. Mesenchymal Stem Cell Group, Department of Haematology, SA Pathology Adelaide and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Lachlan Cooper,

    1. Mesenchymal Stem Cell Group, Department of Haematology, SA Pathology Adelaide and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Danijela Menicanin,

    1. Mesenchymal Stem Cell Group, Department of Haematology, SA Pathology Adelaide and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Ian H Parkinson,

    1. Bone and Joint Research Laboratory, SA Pathology, Adelaide, Australia
    Search for more papers by this author
  • John D Codrington,

    1. Bone and Joint Research Laboratory, SA Pathology, Adelaide, Australia
    2. School of Mechanical Engineering, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Kate Vandyke,

    1. Myeloma Research Program, Department of Haematology, Centre for Cancer Biology, SA Pathology and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Andrew CW Zannettino,

    1. Myeloma Research Program, Department of Haematology, Centre for Cancer Biology, SA Pathology and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Simon A Koblar,

    1. School of Molecular and Biomedical Science, School of Medicine, Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    Search for more papers by this author
  • Natalie A Sims,

    1. Bone Cell Biology and Disease Unit, St Vincent's Institute of Medical Research and Department of Medicine at St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
    Search for more papers by this author
  • Koichi Matsuo,

    1. Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
    Search for more papers by this author
  • Stan Gronthos

    Corresponding author
    1. Mesenchymal Stem Cell Group, Department of Haematology, SA Pathology Adelaide and Centre for Stem Cell Research/Robinson Institute, University of Adelaide, Adelaide, Australia
    2. School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia
    • Institute of Medical and Veterinary Science, South Australia, Department of Haematology, Frome Road, Adelaide, South Australia 5000, Australia.
    Search for more papers by this author

Abstract

Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones. © 2013 American Society for Bone and Mineral Research.

Ancillary