Extracellular phosphate (Pi) has been shown to act as a signaling molecule capable of altering gene expression and cellular function during osteoblastic differentiation. In this study, we investigated whether Pi regulates expression of bone morphogenetic protein (BMP)-2, a crucial regulator of osteogenic differentiation, and explored the signaling pathway involved using human dental pulp cells and human periodontal ligament cells. We found that Pi increased BMP-2 gene expression. Experiments using signaling inhibitors revealed that the increase in BMP-2 expression was dependent on the cAMP/protein kinase A signaling pathway. We also showed that Pi activates the ERK1/2, and treatment with PD98059, an ERK1/2 inhibitor, suppressed Pi-mediated BMP-2 increase, indicating that activation of the ERK1/2 pathway is required for this Pi-mediated response. These findings demonstrate a novel ability of Pi to stimulate BMP-2 via cAMP/protein kinase A and ERK1/2 pathways.
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