The Osteoconductivity of Biomaterials Is Regulated by Bone Morphogenetic Protein 2 Autocrine Loop Involving α2β1 Integrin and Mitogen-Activated Protein Kinase/Extracellular Related Kinase Signaling Pathways

It is critical to understand the complex interactions between cells and scaffolds for a successful tissue engineering approach for bone regeneration. Beyond providing structural support for the cells, synthetic scaffolds act together with some soluble biofactors through intracellular signaling pathways to provide the appropriate clues for cells to form bone tissue. The aim of this study was to investigate the mechanism by which beta-tricalcium phosphate (beta-TCP), a clinically used bone graft substitute, exerts its osteoconductivity on primary human osteoblasts. Culturing human osteoblasts on beta-TCP scaffold for 1 and 7 days induced gene expression of bone morphogenetic protein 2 (BMP2) and its receptors and activated its downstream Smad1/5 signaling pathway, which were orchastrated with induced osteoblastic differentiation. Blocking BMP2 activity by its inhibitor (Noggin) led to the abrogation of osteoblastic differentiation and partially inhibited Smad1/5 signaling pathway. Finally, blocking alpha 2 beta 1 integrin or inhibiting mitogen-activated protein kinase/extracellular related kinase signaling pathway attenuated the induction of gene expression of BMP2 and its receptors and the activation of Smad1/5 signaling pathway. We concluded that beta-TCP scaffold promotes osteoblastic differentiation by a BMP2 autocrine loop, a process involving alpha 2 beta 1 integrin and mitogen-activated protein kinase/extracellular related kinase signaling pathways. The findings of this study might provide a useful principle for fabricating or designing an ideal scaffold for bone tissue engineering.