Research Article

Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice

  1. Xing Shen1,2,
  2. Chao Wan3,
  3. Girish Ramaswamy4,
  4. Mahendra Mavalli3,
  5. Ying Wang3,
  6. Craig L. Duvall5,
  7. Lian Fu Deng2,
  8. Robert E. Guldberg5,
  9. Alan Eberhart4,
  10. Thomas L. Clemens3,
  11. Shawn R. Gilbert2,*

Article first published online: 31 MAR 2009

DOI: 10.1002/jor.20886

Issue

Journal of Orthopaedic Research

Journal of Orthopaedic Research

Volume 27, Issue 10, pages 1298–1305, October 2009

Additional Information

How to Cite

Shen, X., Wan, C., Ramaswamy, G., Mavalli, M., Wang, Y., Duvall, C. L., Deng, L. F., Guldberg, R. E., Eberhart, A., Clemens, T. L. and Gilbert, S. R. (2009), Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J. Orthop. Res., 27: 1298–1305. doi: 10.1002/jor.20886

Author Information

  1. 1

    Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Jiao Tong University, School of Medicine, Shanghai, People's Republic of China

  2. 2

    Department of Surgery, Division of Orthopedic Surgery, University of Alabama at Birmingham, 1600 7th Avenue South, ACC Suite 316, Birmingham, Alabama

  3. 3

    Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233

  4. 4

    Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama

  5. 5

    Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia

*Department of Surgery, Division of Orthopedic Surgery, University of Alabama at Birmingham, 1600 7th Avenue South, ACC Suite 316, Birmingham, Alabama, T: 205-939-5385; F: 205-939-9833.

Publication History

  1. Issue published online: 14 SEP 2009
  2. Article first published online: 31 MAR 2009
  3. Manuscript Accepted: 24 FEB 2009
  4. Manuscript Received: 20 AUG 2008

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Keywords:

  • hypoxia inducible factor;
  • fracture healing;
  • vascularity;
  • prolyl hydroxylase inhibitor

Abstract

Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during development and tissue repair. Small molecule inhibitors of the prolyl hydroxylase enzyme (PHD), the key enzyme responsible for degrading HIF-1, have been shown to activate HIF-1, and are effective in inducing angiogenesis. Here we examined the effects of several commercially available PHD inhibitors on bone marrow mesenchymal stromal cells (MSCs) in vitro and in a stabilized fracture model in vivo. Three PHD inhibitors [Desferrioxamine (DFO), L-mimosine (L-mim), and Dimethyloxalylglycine (DMOG)] effectively activated a HIF-1 target reporter, induced expression of vascular endothelial growth factor (VEGF) mRNA in vitro, and increased capillary sprouting in a functional angiogenesis assay. DFO and DMOG were applied by direct injection at the fracture site in a stabilized murine femur fracture model. PHD inhibition increased the vascularity at 14 days and increased callus size as assessed by microCT at 28 days. These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1298–1305, 2009

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