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The treatment of nonunions with application of BMP-7 increases the expression pattern for angiogenic and inflammable cytokines: a matched pair analysis

Authors Haubruck P, Kammerer A, Korff S, Apitz P, Xiao K, Büchler A, Biglari B, Zimmermann G, Daniel V, Schmidmaier G, Moghaddam A

Received 15 April 2016

Accepted for publication 14 June 2016

Published 22 September 2016 Volume 2016:9 Pages 155—165


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Ning Quan

Patrick Haubruck,1 Andreas Kammerer,1 Sebastian Korff,1 Philipp Apitz,1 Kai Xiao,2 Axel Büchler,1 Bahram Biglari,3 Gerald Zimmermann,4 Volker Daniel,5 Gerhard Schmidmaier,1 Arash Moghaddam1

1Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Trauma and Reconstructive Surgery, Heidelberg University Hospital, HTRG – Heidelberg Trauma Research Group, Heidelberg, Germany; 2Department of Orthopedics Wuhan, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Paraplegiology, Berufsgenossenschaftliche Unfallklinik Ludwigshafen, Ludwigshafen, 4Department for Trauma Surgery, Theresienkrankenhaus und St. Hedwigs-Klinik GmbH, Mannheim, 5Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany

Abstract: The local application of bone morphogenetic protein-7 (BMP-7) in combination with the transplantation of autologous bone graft improves the outcome in nonunion treatment; however, the specific reasons remain unclear. In this study, we sought to determine if the local application of  BMP-7 contributes to improved bone regeneration in nonunion therapy by modulation of the angiogenic and inflammable cytokine expression patterns of the early inflammation response. Therefore, we utilized the analysis of serological cytokine expression patterns. As a matched pair analysis, best-fitting patients who were treated with transplantation of autologous bone graft (G1, n=10) were compared with patients who were treated with additional application of BMP-7 (G2, n=10). The changes in the cytokine expression patterns were monitored and correlated to clinical data of bone healing. Significant differences in angiogenesis potential (vascular endothelial growth factor [VEGF] serum levels) could be found in the first days after surgery (P<0.05). Furthermore, the increase and absolute amount of  VEGF levels in the BMP-7 group were considerably higher than in the control group during the first 2 weeks after surgery. The expression pattern of inflammable cytokines showed noticeable differences in the time point of significant elevated levels, in particular, inflammable cytokines showed an earlier peak in G2. Furthermore, interleukin-6 was significantly elevated within the first week only, comparing G2 to G1 (P<0.05). Our findings indicate that BMP-7 induces an early and more intense expression of VEGF via a direct and postulated indirect pathway, thereby providing a favorable environment for bone healing. Moreover, application of BMP-7 leads to an earlier expression of known proinflammatory cytokines. The results of this study show that application of BMP-7 leads to costimulatory effect on both angiogenic and inflammable cytokine expression patterns that may serve as a possible stimulus for bone regeneration.

Keywords: bone regeneration, angiogenesis, VEGF, IL-6, inflammation, cytokines

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