The systemic angiogenic response during bone healing |
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Authors: | Stefan Weiss Gerald Zimmermann Thomas Pufe Deike Varoga Philipp Henle |
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Institution: | (1) Department of Orthopaedics, University of Heidelberg, Heidelberg, Germany;(2) Berufsgenossenschaftliche Unfallklinik, Ludwigshafen am Rhein, Germany;(3) Department of Anatomy and Cellular Biology, University Hospital Aachen, Aachen, Germany;(4) Department of Orthopaedic Surgery, University Hospital of Schleswig-Holstein, Kiel, Germany;(5) Department of Orthopaedic Surgery, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland |
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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.
Authors Stefan Weiss and Gerald Zimmermann contributed equally to this work. |
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Keywords: | Fracture healing Endochondral bone formation Angiogenesis Nonunion |
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