Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.
Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E2 promotes both bone resorption and bone formation. By infusing PGE2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor alpha1 (Runx2/Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.
Yoshida
Keiji
K
Department of Pharmacology, Faculty of Medicine, Institute for Virus Research, Kyoto University, Kyoto 606-8501, Japan.
Oida
Hiroji
H
Kobayashi
Takuya
T
Maruyama
Takayuki
T
Tanaka
Masaharu
M
Katayama
Teruaki
T
Yamaguchi
Kojiro
K
Segi
Eri
E
Tsuboyama
Tadao
T
Matsushita
Mutsumi
M
Ito
Kosei
K
Ito
Yoshiaki
Y
Sugimoto
Yukihiko
Y
Ushikubi
Fumitaka
F
Ohuchida
Shuichi
S
Kondo
Kigen
K
Nakamura
Takashi
T
Narumiya
Shuh
S
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000517:prevention & control; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype
C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone