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Department of Biochemistry, Showa University School of Dentistry (Te.S., C.M., M.I., Ta.S.), 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555; Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science (C.M., M.I.), Tokyo 192-0392; Discovery Research Laboratory I, Minase Research Institute, Ono Pharmaceutical Co. Ltd. (T.M.), Osaka 618-8585; and Department of Physiological Chemistry, Faculty of Pharmaceutical Science (Y.S., A.I.), Kyoto 606-8501; and Department of Pharmacology, Faculty of Medicine (F.U., S.N.), Kyoto University, Kyoto 606-8501, Japan
Address all correspondence and requests for reprints to: Dr. Tatsuo Suda, Department of Biochemistry, Showa University School of Dentistry, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
PGE2 functions as a potent stimulator of bone resorption. The action of PGE2 is thought to be mediated by some PGE receptor subtypes present in osteoblastic cells. In this study, we examined the involvement of PGE receptor subtypes, EP1, EP2, EP3, and EP4, in PGE2-induced bone resorption using specific agonists for the respective EPs. In mouse calvaria cultures, EP4 agonist markedly stimulated bone resorption, but its maximal stimulation was less than that induced by PGE2. EP2 agonist also stimulated bone resorption, but only slightly. EP1 and EP3 agonists did not stimulate it at all. RT-PCR showed that osteoblastic cells isolated from newborn mouse calvaria expressed all of the EPs messenger RNA (mRNA). Both EP2 agonist and EP4 agonist induced cAMP production and the expression of osteoclast differentiation factor (ODF) mRNA in osteoblastic cells. Simultaneous addition of EP2 and EP4 agonists cooperatively induced cAMP production and ODF mRNA expression. In mouse bone marrow cultures, EP2 and EP4 agonists moderately induced osteoclast formation, but the simultaneous addition of the two agonists cooperatively induced it, similar to that by PGE2. In calvaria culture from EP4 knockout mice, a marked reduction in bone resorption to PGE2 was found. In EP4 knockout mice, EP4 agonist failed to induce bone resorption, but EP2 agonist slightly, but significantly, induced bone resorption. These findings suggest that PGE2 stimulates bone resorption by a mechanism involving cAMP and ODF, which is mediated mainly by EP4 and partially by EP2.
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M. Takami, N. Takahashi, N. Udagawa, C. Miyaura, K. Suda, J.-T. Woo, T. J. Martin, K. Nagai, and T. Suda Intracellular Calcium and Protein Kinase C Mediate Expression of Receptor Activator of Nuclear Factor-{{kappa}}B Ligand and Osteoprotegerin in Osteoblasts Endocrinology, December 1, 2000; 141(12): 4711 - 4719. [Abstract] [Full Text] [PDF]
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A. Ogasawara, T. Arakawa, T. Kaneda, T. Takuma, T. Sato, H. Kaneko, M. Kumegawa, and Y. Hakeda Fluid Shear Stress-induced Cyclooxygenase-2 Expression Is Mediated by C/EBP beta , cAMP-response Element-binding Protein, and AP-1 in Osteoblastic MC3T3-E1 Cells J. Biol. Chem., March 2, 2001; 276(10): 7048 - 7054. [Abstract] [Full Text] [PDF]
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K. Yoshida, H. Oida, T. Kobayashi, T. Maruyama, M. Tanaka, T. Katayama, K. Yamaguchi, E. Segi, T. Tsuboyama, M. Matsushita, et al. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation PNAS, April 2, 2002; 99(7): 4580 - 4585. [Abstract] [Full Text] [PDF]
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 S. L. Borgland, M. Connor, R. M. Ryan, H. J. Ball, and M. J. Christie Prostaglandin E2 inhibits calcium current in two sub-populations of acutely isolated mouse trigeminal sensory neurons J. Physiol., March 1, 2002; 539(2): 433 - 444. [Abstract] [Full Text] [PDF]
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