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

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.

A Preliminary Study of Contrast-Enhanced Ultrasound (CEUS) and Cytokine Expression Analysis (CEA) as Early Predictors for the Outcome of Tibial Non-Union Therapy

“…The inclusion and exclusion criteria were chosen to reduce possible confounders and to increase the consistency and thereby quality and reliability of our data and have been established in multiple previous studies [ 11 , 13 , 15 ].…”

“…In a recent study, CEUS has been shown to be effective in monitoring the vascularity of non-unions [ 9 ] and distinguishing preoperatively based on the microperfusion between infected and non-infected non-unions [ 9 ]. In addition, bone regeneration correlates with changes in the serum expression pattern of pro-angiogenic and pro-inflammatory cytokines [ 2 , 13 , 14 , 15 ]. Recently, the systemic analysis of markers associated with bone regeneration assessed by measurement of serum cytokine expression analysis (CEA) was established as a valid method in the timely evaluation of biological processes occurring during fracture healing and bone regeneration [ 2 , 13 , 14 , 15 ].…”

“…In addition, bone regeneration correlates with changes in the serum expression pattern of pro-angiogenic and pro-inflammatory cytokines [ 2 , 13 , 14 , 15 ]. Recently, the systemic analysis of markers associated with bone regeneration assessed by measurement of serum cytokine expression analysis (CEA) was established as a valid method in the timely evaluation of biological processes occurring during fracture healing and bone regeneration [ 2 , 13 , 14 , 15 ]. Promising initial findings [ 2 , 9 , 13 , 16 ] support the predictive potential of both local (CEUS) and systemic (serum cytokine analysis) diagnostic modalities.…”

“…Recently, the systemic analysis of markers associated with bone regeneration assessed by measurement of serum cytokine expression analysis (CEA) was established as a valid method in the timely evaluation of biological processes occurring during fracture healing and bone regeneration [ 2 , 13 , 14 , 15 ]. Promising initial findings [ 2 , 9 , 13 , 16 ] support the predictive potential of both local (CEUS) and systemic (serum cytokine analysis) diagnostic modalities. However, no other study exists investigating the combined diagnostic potential of these novel radiation-free tools.…”

Sub‐clinical dose of bone morphogenetic protein‐2 does not precipitate rampant, sustained inflammatory response in bone wound healing

“…4,5 While the gold standard intervention for these cases is the autologous bone graft, limited tissue available for harvest, the creation of a second surgical site, and donor site co-morbidity have necessitated the search for alternative therapeutic strategies. [5][6][7][8][9][10][11][12][13][14] One strategy that has become particularly prominent is the application of exogenous recombinant human bone morphogenetic protein 2 (rhBMP-2) via an absorbable collagen sponge (ACS). 15,16 This product currently has four United States Food and Drug Administration (FDA) approved clinical indications: spinal fusions, tibial shaft fractures, maxillary sinus lift, and alveolar ridge augmentations.…”