Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats

Prostaglandin E-2 (PGE(2)) is essential for fracture healing. Systemic administration of EP4 ligands such as PGE(2) and other synthetic EP4 agonists appears to transduce anabolic signals by binding to receptor EP4. Therefore, the present study was designed to test whether administration of EP4 agonist accelerates the healing of drill-hole injury in the femoral diaphysis. After surgery, a total of 128 Wistar rats, at the age of 12 weeks, were assigned to basal control (n = 8), and three groups with respective doses of 0 (vehicle control), 10 (low-dose), and 30 (high-dose) mug/kg body weight of the agent were subcutaneously injected twice a day. Femoral specimens were obtained at 0, 5, 7, 14, 2 1, and 28 days. In EP4 agonist-treated groups, the total bone volume of the regenerating bone in the defect did not significantly differ, but the regenerated cortical bone volume measured by histomorphometry and cortical bone mineral content (Ct. BMC) by pQCT dose-dependently increased at 14 and 21 days compared to the control. In the high-dose group, the value of osteoclast surface significantly increased compared with that in the control at 14 days. Expression levels of osteocalcin and TRAP mRNAs in the injured tissue increased at 14 days. Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high-dose group. The bone mineral values of the lumbar bone at 28 days, measured by DXA, did not differ in the three groups. These data indicated that systemic administration of EP4 agonist ONO-4819.CD accelerated cortical bone healing after drill-hole injury by upregulating the local turnover of the regenerating bone. (C) 2004 Elsevier Inc. All rights reserved.