The bone morphogenetic protein-2/7 heterodimer is a stronger inducer of bone regeneration than the individual homodimers in a rat spinal fusion model

Abstract

Background context: Bone morphogenetic proteins (BMPs) are a group of dimeric growth factors that belong to the transforming growth factor super family and are capable of eliciting new bone formation. Previous studies have suggested that the coexpression of two different BMP genes in a cell can result in the production of BMP heterodimers that are more potent than homodimers. However, because of the difficulty in optimizing the level of BMP gene expression, the coexpression of two different BMP genes also produces BMP homodimers as a by-product. These homodimers could, in theory, interact with the heterodimers.

Purpose: To elucidate the effects of a BMP-2/7 heterodimer, which were investigated in depth using purified BMP-2/7 heterodimers, BMP-2 homodimers, and BMP-7 homodimers in a rat spinal fusion model.

Methods: Bilateral posterolateral fusion at L4-L5 was performed in four different groups: control group animals were implanted with collagen carriers alone; BMP-7 group animals with collagen carriers+1 μg of BMP-7 homodimer; BMP-2 group animals with collagen carriers+1 μg of BMP-2 homodimer; and BMP-2/7 group animals with collagen carriers+1 μg of the BMP-2/7 heterodimer. The following assessments were performed: bone microstructural analysis of the fusion mass and tissue volume (TV) with microcomputed tomography (micro-CT); fusion assessment with manual palpation testing and three-dimensional CT images; and bone histomorphometrical analysis of the fusion mass.

Results: The fusion scores, as determined by radiography, and the TV of the newly formed bone, as determined by micro-CT, were significantly higher in the BMP-2/7 heterodimer group than the other groups (p<.0001). The microstructural indices of the newly formed bone did not differ between the groups. Moreover, histologic analysis of the fused spines revealed that the formation of the trabecular bone bridging the transverse process was the highest in this group.

Conclusions: This study demonstrated that BMP-2/7 heterodimer is a stronger inducer of bone regeneration than BMP-2 or -7 homodimers. The use of a purified BMP-2/7 heterodimer may represent an efficient alternative to the current clinical use of BMP-2 or -7 homodimers. Further studies as to the side effects of BMP-2/7 heterodimer are required.

Keywords: BMP heterodimer; BMP homodimer; Bone morphogenetic protein; Bone regeneration; Cytokine therapy; Spinal fusion.