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The systemic angiogenic response during bone healing

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Archives of Orthopaedic and Trauma Surgery Aims and scope Submit manuscript

Abstract

Introduction

Angiogenesis is known to be a critical and closely regulated step during bone formation and fracture healing driven by a complex interaction of various cytokines. Delays in bone healing or even nonunion might therefore be associated with altered concentrations of specific angiogenic factors. These alterations might in turn be reflected by changes in serum concentrations.

Method

To determine physiological time courses of angiogenic cytokines during fracture healing as well as possible changes associated with failed consolidation, we prospectively collected serum samples from patients who had sustained surgical treatment for a long bone fracture. Fifteen patients without fracture healing 4 months after surgery (nonunion group) were matched to a collective of 15 patients with successful healing (union group). Serum concentrations of angiogenin (ANG), angiopoietin 2 (Ang-2), basic fibroblast growth factor (bFGF), platelet derived growth factor AB (PDGF-AB), pleiotrophin (PTN) and vascular endothelial growth factor (VEGF) were measured using enzyme linked immunosorbent assays over a period of 24 weeks.

Results

Compared to reference values of healthy uninjured controls serum concentrations of VEGF, bFGF and PDGF were increased in both groups. Peak concentrations of these cytokines were reached during early fracture healing. Serum concentrations of bFGF and PDGF-AB were significantly higher in the union group at 2 and 4 weeks after the injury when compared to the nonunion group. Serum concentrations of ANG and Ang-2 declined steadily from the first measurement in normal healing fractures, while no significant changes over time could be detected for serum concentrations of these factures in nonunion patients. PTN serum levels increased asymptotically over the entire investigation in timely fracture healing while no such increase could be detected during delayed healing.

Conclusion

We conclude that fracture healing in human subjects is accompanied by distinct changes in systemic levels of specific angiogenic factors. Significant alterations of these physiologic changes in patients developing a fracture nonunion over time could be detected as early as 2 (bFGF) and 4 weeks (PDGF-AB) after initial trauma surgery.

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Acknowledgments

Funding of this investigation was provided by grants from the Deutsche Forschungsgemeinschaft, DFG (WE 2675/1-1, Pu 214/3-2, Pu 214/4-2, Pu 214/5-2, SFB 617) and a grant from the Orthopaedic University Hospital Heidelberg.

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Authors and Affiliations

  1. Department of Orthopaedics, University of Heidelberg, Heidelberg, Germany

    Stefan Weiss & Philipp Henle

  2. Berufsgenossenschaftliche Unfallklinik, Ludwigshafen am Rhein, Germany

    Gerald Zimmermann

  3. Department of Anatomy and Cellular Biology, University Hospital Aachen, Aachen, Germany

    Thomas Pufe

  4. Department of Orthopaedic Surgery, University Hospital of Schleswig-Holstein, Kiel, Germany

    Deike Varoga

  5. Department of Orthopaedic Surgery, Inselspital, Bern University Hospital, and University of Bern, 3010, Bern, Switzerland

    Philipp Henle

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  1. Stefan Weiss
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  5. Philipp Henle
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Correspondence to Philipp Henle.

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Authors Stefan Weiss and Gerald Zimmermann contributed equally to this work.

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Weiss, S., Zimmermann, G., Pufe, T. et al. The systemic angiogenic response during bone healing. Arch Orthop Trauma Surg 129, 989–997 (2009). https://doi.org/10.1007/s00402-008-0777-5

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