Beta-tricalcium phosphate (beta-TCP) has been clinically used as a bone graft substitute for decades because of its excellent osteoconductivity. However, the exact mechanism(s) by which beta-Tcp exerts osteoconductivity are not fully documented. This study was aimed to investigate the molecular mechanism(s) by which beta-TCP modulates the biological response of primary human osteoblasts (HOBs). It was showed that HOBs seeded into the beta-TCP scaffolds expressed significantly higher levels of osteogenic genes, compared to those cultured on tissue culture plastic; meanwhile these cells showed 7-fold increase in alpha 2 integrin subunit gene expression and the activation of the mitogen-activated protein kinase (MAPK)/extracellular related kinase (ERK) signaling pathway. In addition, the osteogenic conduction by beta-Tcp scaffolds was attenuated directly by inhibiting MAPK/ERK or indirectly by blocking the alpha 2 beta 1 integrin signaling pathway. We concluded that beta-TCP scaffold exerts osteoconductivity through alpha 2 beta 1 integrin and down-stream MAPK/ERK signaling pathway, suggesting a feasible approach to consider when designing or fabricating the scaffolds for bone tissue engineering. (C) 2010 Elsevier Inc. All rights reserved.