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. 2016 Sep 22:9:155-165.
doi: 10.2147/JIR.S110621. eCollection 2016.

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

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 Moghaddam  1
Affiliations

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

Patrick Haubruck et al. J Inflamm Res. .

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: IL-6; VEGF; angiogenesis; bone regeneration; cytokines; inflammation.

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Figures

Figure 1
Figure 1
A timeline of the protocol for taking blood samples throughout this study. Notes: Blood was drained from each patient 1d p and 2d, 1w, 2w, 4w, 6w, and 12w after surgery. Abbreviations: p, preoperative; d, day(s); w, week(s).
Figure 2
Figure 2
Evaluation of the expression pattern of VEGF after nonunion treatment. Notes: (A) Serum concentrations of VEGF in pg/mL 1d before and 2d, 1w, 2w, 4w, 6w, and 12w after surgery. Significant differences are indicated by a star (P<0.05, whiskers are SD). (B) Box plot after 2d to 2w of surgery. Whiskers demonstrate one-quarter of the sample. Stars indicate significant differences comparing the study and control groups at the time point (P<0.05). Abbreviations: VEGF, vascular endothelial growth factor; p, preoperative; d, day(s); w, week(s); SD, standard deviation; BMP-7, bone morphogenetic protein-7; G1, patients who were treated with transplantation of autologous bone graft; G2, patients who were treated with additional application of BMP-7.
Figure 3
Figure 3
Evaluation of the expression pattern of TNF-α and IL-8 after nonunion treatment. Notes: (A) Serum concentrations of TNF-α in pg/mL 1d before and 2d, 1w, 2w, 4w, 6w, and 12w after surgery. (B) Serum concentrations of IL-8 in pg/mL 1d before and 2d, 1w, 2w, 4w, 6w, and 12w after surgery. Peak of IL-8 in the control group could be found after 4w of surgery. Peak of IL-8 in the study group was found within the first 2w after surgery. Abbreviations: TNF-α, tumor necrosis factor-α; p, preoperative; d, day(s); w, week(s); SD, standard deviation; IL-8, interleukin-8; BMP-7, bone morphogenetic protein-7; G1, patients who were treated with transplantation of autologous bone graft; G2, patients who were treated with additional application of BMP-7.
Figure 4
Figure 4
Evaluation of the expression pattern of IL-6 after nonunion treatment. Notes: (A) Serum concentrations of IL-6 in pg/mL 1d before and 2d, 1w, 2w, 4w, 6w, and 12w after surgery. Significant differences are indicated by a star (P<0.05, whiskers are SEM). (B) Box plot in a logarithmic scale on the y-axis of day before to 1w after surgery. Whiskers demonstrate one-quarter of the sample. Stars indicate significant differences comparing the study and control group at the time point (P<0.05). Abbreviations: IL-6, interleukin-6; p, preoperative; d, day(s); w, week(s); SEM, standard error of the mean; BMP-7, bone morphogenetic protein-7; G1, patients who were treated with transplantation of autologous bone graft; G2, patients who were treated with additional application of BMP-7.
Figure 5
Figure 5
Analysis of the serological inflammable parameters after nonunion treatment. Notes: (A) Serum concentrations of CRP in mg/L 1d before and 2d, 1w, and 2w after surgery. (B) Serum concentrations of leukocytes in l,000/nL 1d before and 2d, 1w, and 2w after surgery. Abbreviations: CRP, C-reactive protein; p, preoperative; d, day(s); w, week(s); BMP-7, bone morphogenetic protein-7; G1, patients who were treated with transplantation of autologous bone graft; G2, patients who were treated with additional application of BMP-7.
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