SUMMARY Zebrafish fully regenerate lost bone, including after fin amputation, through a process mediated by dedifferentiated, lineage-restricted osteoblasts. Mechanisms controlling the osteoblast regenerative program from its initiation through reossification are poorly understood. We show that fin amputation induces a Wnt/β-catenin-dependent epithelial to mesenchymal transformation (EMT) of osteoblasts in order to generate proliferative Runx2+ preosteoblasts. Localized Wnt/β-catenin signaling maintains this progenitor population toward the distal tip of the regenerative blastema. As they become proximally displaced, preosteoblasts upregulate sp7 and subsequently mature into re-epithelialized Runx2−/sp7+ osteoblasts that extend preexisting bone. Auto-crine bone morphogenetic protein (BMP) signaling promotes osteoblast differentiation by activating sp7 expression and counters Wnt by inducing Dickkopf-related Wnt antagonists. As such, opposing activities of Wnt and BMP coordinate the simultaneous demand for growth and differentiation during bone regeneration. This hierarchical signaling network model provides a conceptual framework for understanding innate bone repair and regeneration mechanisms and rationally designing regenerative therapeutics.
Previous research has raised substantial controversy over the synergistic effects of exogenous growth factors, BMP-2 and bFGF, when used together for the treatment of bony defects. Thus, this study evaluated the effects of BMP-2 and bFGF at specified dose ratio composited with n-HA/PU40, a porous scaffold material, for repairing femoral defect in rats. Four weeks after implantation of this composite system, tissue specimens were collected for histological, immunohistochemical examinations, and µ-CT scanning. The results showed that the group DUAL/BMSCs with both the factors had better effect on repairing bone defects than the other four groups in terms of new bone formation and bone-scaffold bonding, suggesting crosstalk between these growth factors during early bone regeneration. This work demonstrates that provided that there is effective contact between cells and active proteins in the defect area, the controlled release of bFGF and BMP-2 have positive synergistic effects on early bone formation in the defect area. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 659-668, 2016.
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