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Abstract: Bone morphogenetic proteins (BMPs) are potent bone inducers used clinically to enhance fracture repair. BMPs have been shown to be produced in the fracture callus; however, the comparative expression of BMPs and BMP signaling components has only been partially examined at the cellular level. The aim of the present study was to establish a detailed spatiotemporal localization of BMPs and BMP signaling components in mouse models of stabilized and nonstabilized fractures. During healing of nonstabilized fractures, which occurs via endochondral ossification, BMP2, 3, 4, 5, and 8, noggin, BMPRIA, BMPRII, and pSmad 1/5/8 were immunolocalized in the activated periosteum as early as 3 days after fracture. BMP2, 4, 5, 6, 7, and 8 and noggin were also found in isolated inflammatory cells within granulation tissue during the early stages of repair, but not BMP receptors and effectors. During the soft callus phase of repair, all BMPs and BMP signaling components were detected in chondrocytes with various intensities of staining depending on the stage of chondrocyte differentiation and their location in the callus. The strongest staining was observed in hypertrophic chondrocytes with decreased intensity during the hard callus phase of repair. All BMPs and components of the BMP pathway were detected in osteoblasts and osteocytes within new bone, with strongest intensity of immunoreaction reported during the early soft callus phase followed by decreasing intensity during the hard callus phase of repair. Most components of the BMP pathway were also detected in endothelial cells associated with new bone. In stabilized fractures that heal strictly via intramembranous ossification, BMPs and BMP antagonists were detected in isolated inflammatory cells and BMP signaling components were not detectable in osteoblasts or osteocytes within new bone. In conclusion, the BMP signaling pathway is primarily activated during fracture healing via endochondral ossification, suggesting that this pathway may influence the mode of healing during the recruitment of skeletal progenitors. [Copyright &y& Elsevier]

Background context The ideal tissue-engineered solution for any bone graft substitute is to assist in the rapid formation of bone and facilitate fusion. Purpose The present study aims to evaluate this E-BMP-2 (Escherichia coli-derived human bone morphogenetic protein-2) in ovine posterolateral lumbar fusion (PLF) to examine the influence of dose and overall performance in a model with similar graft size and diffusive challenges to the human. Study design/setting In vivo large animal model study. Methods An adult ovine PLF was performed in 30 animals with groups of E-BMP-2 with a beta-tricalcium phosphate (β-TCP) carrier at three different dosages, β-TCP alone, and autograft from the iliac crest. The fusions were assessed by radiography (X-ray and microcomputed tomography), mechanical testing, and hard-tissue histology with bone labels at 6, 8, and 10 weeks along with routine paraffin histology at 12 weeks. Results Results showed increasing new bone and fusion rate with E-BMP-2 dose, whereas β-TCP alone was largely resorbed and did not achieve fusion in this model at 12 weeks. Autograft showed similar grading for the amount of bone between the transverse processes but a lower fusion rate than β-TCP/E-BMP-2 groups. Bone labels revealed new bone formation at all time points for the E-BMP2 groups, whereas the autograft group showed active bone formation at 10 weeks. Beta-tricalcium phosphate displayed reliable incorporation into the decorticated host bone, whereas limited new bone was found between the transverse processes. At the center of the fusion mass, increased E-BMP-2 dose led to increased incorporation of β-TCP by new bone. Conclusions These results suggest that E-BMP-2 was capable of producing posterolateral fusion in the ovine model that is equal to or superior to autologous graft in terms of fusion rate and mechanical strength. E-BMP-2 dose had considerable influence on β-TCP granule resorption. [ABSTRACT FROM AUTHOR]