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Infection and Immunity, December 2000, p. 6819-6825, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Impaired Bone Resorption by Lipopolysaccharide In Vivo in Mice Deficient in the Prostaglandin E Receptor EP4 Subtype

Yoko Sakuma,1 Kiyoshi Tanaka,1,* Michio Suda,1 Yasato Komatsu,1 Akihiro Yasoda,1 Masako Miura,1 Ami Ozasa,1 Shuh Narumiya,2 Yukihiko Sugimoto,3 Atsushi Ichikawa,3 Fumitaka Ushikubi,4 and Kazuwa Nakao1

Department of Medicine and Clinical Science1 and Department of Cell Pharmacology, Graduate School of Medicine,2 and Physiological Chemistry, Faculty of Pharmaceutical Sciences,3 Kyoto University, Sakyo, Kyoto, and Physiological Chemistry, Asahikawa Medical University, Asahikawa,4 Japan

Received 20 December 1999/Returned for modification 9 March 2000/Accepted 1 August 2000

In a previous study we showed that the involvement of EP4 subtype of the prostaglandin E (PGE) receptor is crucial for lipopolysaccharide (LPS)-induced osteoclast formation in vitro. The present study was undertaken to test whether EP4 is actually associated with LPS-induced bone resorption in vivo. In wild-type (WT) mice, osteoclast formation in vertebrae and tibiae increased 5 days after systemic LPS injection, and urinary excretion of deoxypyridinoline, a sensitive marker for bone resorption, statistically increased 10 days after injection. In EP4 knockout (KO) mice, however, LPS injection caused no significant changes in these parameters throughout the experiment. LPS exposure for 4 h strongly induced osteoclast differentiation factor (ODF) mRNA expression in primary osteoblastic cells (POB) both from WT and EP4 KO mice, and this expression was not inhibited by indomethacin, suggesting prostaglandin (PG) independence. LPS exposure for 24 h further induced ODF expression in WT POB, but not in EP4 KO POB. Indomethacin partially inhibited ODF expression in WT POB, but not in EP4 KO POB. These data suggest that ODF is induced both PG dependently and PG independently. LPS exposure for 24 h induced slightly greater osteoclastgenesis inhibitory factor (OCIF) mRNA expression in EP4 KO than in WT POB. These findings suggest that the reduced ODF expression and apparently increased OCIF expression also are responsible for the markedly reduced LPS-induced osteoclast formation in EP4 KO mice. Our results show that the EP4 subtype of the PGE receptor is involved in LPS-induced bone resorption in vivo also. Since LPS is considered to be largely involved in bacterially induced bone loss, such as in periodontitis and osteomyelitis, our study is expected to help broaden our understanding of the pathophysiology of these conditions.

* Corresponding author. Mailing address: Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, 54, Shogoin-kawaharacho, Sakyo, Kyoto 606-8507, Japan. Phone: 81-75-753-7509. Fax: 81-75-771-9452. E-mail: ktanaka{at}koshien.ac.jp.

Infection and Immunity, December 2000, p. 6819-6825, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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