Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation

Bone morphogenetic proteins (BMPs) were originally isolated based on their ability to induce ectopic cartilage and bone formation. The agents to promote the local bone formation with BMP would be beneficial to promote bone repair and to shorten the treatment period. For this purpose, we have examined ONO-4819, which is a prostaglandin (PG) E2 EP4 receptor selective agonist (EP4A), as a positive modulators for the efficacy of BMPs. In our previous study, the systemic and local (with biodegradable synthetic polymers) administration of EP4A led to a significant augmentation of ossicle mass. But the mechanisms how EP4A accelerates the BMP-mediated bone formation are still unknown. In this study, we have examined how EP4A facilitates the BMP signaling using in vitro system with pluripotent stromal cell line, ST2. The mRNA expressions of Osterix and ALP (a marker enzyme of osteoblastic differentiation) and enzymatic activity of ALP in the ST2 cells were elevated significantly by BMP treatment. This elevation was further elevated by addition of the EP4A. The accelerated BMP action by the EP4A was abolished by pre-treatment with PKA inhibitor.This study suggests that ONO-4819 accelerates BMP-induced osteoblastic differentiation of ST2 cells by stimulating the commitment for osteoblastic lineage. Thus PKA signaling pathway would be the main intracellular signaling pathway of the EP4 for the anabolic effect of bone and mineral metabolisms.