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J. Biol. Chem., Vol. 280, Issue 25, 24035-24042, June 24, 2005

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Prostaglandin E₂ Receptors EP2 and EP4 Are Down-regulated during Differentiation of Mouse Osteoclasts from Their Precursors^*

Yasuhiro Kobayashi, Ikuko Take, Teruhito Yamashita¶, Toshihide Mizoguchi, Tadashi Ninomiya, Toshimi Hattori||, Saburo Kurihara, Hidehiro Ozawa, Nobuyuki Udagawa¶, and Naoyuki Takahashi**

From the Institute for Oral Science, Department of Orthodontics, ^¶Department of Biochemistry, and ^||Department of Pharmacology, Matsumoto Dental University, 1780 Hiro-oka Gobara, Shiojiri, Nagano 399-0781, Japan

Prostaglandin E₂ (PGE₂) has been proposed to be a potent stimulator of bone resorption. However, PGE₂ itself has been shown to directly inhibit bone-resorbing activity of osteoclasts. We examined the role of PGE₂ in the function of mouse osteoclasts formed in vitro. Bone marrow macrophage osteoclast precursors expressed PGE₂ receptors EP1, EP2, EP3, and EP4, and the expression of EP2 and EP4 was down-regulated during osteoclastic differentiation induced by receptor activator of NF-B ligand and macrophage colony-stimulating factor. In contrast, functional EP1 was continuously expressed in mature osteoclasts. PGE₂ as well as calcitonin caused intracellular Ca²⁺ influx in osteoclasts. However, PGE₂ and 17-phenyltrinol-PGE₂ (an EP1 agonist) failed to inhibit actin-ring formation and pit formation by osteoclasts cultured on dentine slices. When EP4 was expressed in osteoclasts using an adenovirus carrying EP4 cDNA, both actin-ring and pit-forming activities of osteoclasts were inhibited in an infectious unit-dependent manner. Treatment of EP4-expressing osteoclasts with PGE₂ further inhibited their actin-ring and pit-forming activities. Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated. Thus, osteoclast precursors down-regulate their own EP2 and EP4 levels during their differentiation into osteoclasts to escape inhibitory effects of PGE₂ on bone resorption.

Received for publication, January 25, 2005 , and in revised form, April 7, 2005.

^* This work was supported in part by Grants-in-aid 16659578 and 12137209 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-oka Gobara, Shiojiri, Nagano 399-0781, Japan. Tel.: 81-263-51-2135; Fax: 81-263-51-2223; E-mail: takahashinao{at}po.mdu.ac.jp.

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				I. Take, Y. Kobayashi, Y. Yamamoto, H. Tsuboi, T. Ochi, S. Uematsu, N. Okafuji, S. Kurihara, N. Udagawa, and N. Takahashi Prostaglandin E2 Strongly Inhibits Human Osteoclast Formation Endocrinology, December 1, 2005; 146(12): 5204 - 5214. [Abstract] [Full Text] [PDF]