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To investigate the mechanism of bone formation by EP4 activation, an osmotic pump was implanted subcutaneously into the backs of rats and an EP4 receptor agonist was administered at a dose of 100 ng/kg/min for up to 28 days. The histology of the femur (including bone marrow) and the serum and/or urinary bone metabolism parameters were examined on Day 0, 1, 3, 5, 7, 14, and Day 28. In EP4 receptor agonist treated-rats, increase of osteoclasts in the metaphysis was observed on Day 1 and the number of osteoblast showed an increase from Day 3. In addition, cancellous bone and endosteal bone formation were observed in the metaphysis and diaphysis from Day 5 and this peaked on Day 28. Serum alkaline phosphatase activity showed a transient decrease on Day 1, but thereafter showed an increase. The Gla-type osteocalcin level showed an increase from Day 1. Moreover, Gla/Glu osteocalcin ratio showed an increase on Day 5. The urinary excretion of deoxypyridinoline increased on Day 3, showed a transient decrease on Day 5, and increased once again from Day 7. These results indicate that EP4 receptor agonist-induced bone formation is related to an increase of osteoclasts at the initial stage and a subsequent increase of osteoblasts.

Prostaglandin E EP4 Receptor Agonist Induces the Bone Formation by an Alteration of the Osteoblast and Osteoclast Dynamic State