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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

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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.

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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.
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f3-jir-9-155: 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.

Mentions: TNF-α was similarly elevated after surgery in both groups (control and study). The mean concentrations of TNF-α in the BMP-7 group peaked 1 week after treatment and returned to preoperative serum levels of 12.0±3.3 pg/mL after 6 weeks (Figure 3A). In contrast to the study group, an initial decrease in the TNF-α serum level was observed in the control group 2 days after surgery. Interestingly, the maximum TNF-α concentration was measured not merely at week 1 but rather 4 weeks after surgery (17.2±2.8 pg/mL). No significant differences could be found in comparing both groups at each time point. However, noticeable differences could be detected in the time point of significant elevated TNF-α levels. In the G2 group, peak values of TNF-α serum levels could be detected on week 1 comparing to peak values of TNF-α serum levels in the G1 group at week 4 (Figure 3A). These data imply an earlier peak in the TNF-α plasma levels of the BMP-7 group than those of the control group by more than 2 weeks.


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

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getmorefigures.php?uid=PMC5036623&req=5

f3-jir-9-155: 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.
Mentions: TNF-α was similarly elevated after surgery in both groups (control and study). The mean concentrations of TNF-α in the BMP-7 group peaked 1 week after treatment and returned to preoperative serum levels of 12.0±3.3 pg/mL after 6 weeks (Figure 3A). In contrast to the study group, an initial decrease in the TNF-α serum level was observed in the control group 2 days after surgery. Interestingly, the maximum TNF-α concentration was measured not merely at week 1 but rather 4 weeks after surgery (17.2±2.8 pg/mL). No significant differences could be found in comparing both groups at each time point. However, noticeable differences could be detected in the time point of significant elevated TNF-α levels. In the G2 group, peak values of TNF-α serum levels could be detected on week 1 comparing to peak values of TNF-α serum levels in the G1 group at week 4 (Figure 3A). These data imply an earlier peak in the TNF-α plasma levels of the BMP-7 group than those of the control group by more than 2 weeks.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus