The Journal of Experimental Medicine
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Published online 12 May 2003 doi:10.1084/jem.20030015
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© Rockefeller University Press, 0022-1007/2003/5/1303 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1303-1310

An Essential Role of Cytosolic Phospholipase A2{alpha} in Prostaglandin E2–mediated Bone Resorption Associated with Inflammation

Chisato Miyaura1, Masaki Inada1, Chiho Matsumoto1, Tomoyasu Ohshiba1, Naonori Uozumi2, Takao Shimizu2 and Akira Ito1

1 Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, and Core Research and Evolutional Science and Technology (CREST) of JST, The University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: tshimizu{at}m.u-tokyo.ac.jp

Prostaglandin E (PGE)2 produced by osteoblasts acts as a potent stimulator of bone resorption. Inflammatory bone loss is accompanied by osteoclast formation induced by bone-resorbing cytokines, but the mechanism of PGE2 production and bone resorption in vivo is not fully understood. Using cytosolic phospholipase A2{alpha} (cPLA2{alpha})-null mice, we examined the role of cPLA2{alpha} in PGE2 synthesis and bone resorption. In bone marrow cultures, interleukin (IL)-1 markedly stimulated PGE2 production and osteoclast formation in wild-type mice, but not in cPLA2{alpha}-null mice. Osteoblastic bone marrow stromal cells induced the expression of cyclooxygenase (COX)-2 and membrane-bound PGE2 synthase (mPGES) in response to IL-1 and lipopolysaccharide (LPS) to produce PGE2. Osteoblastic stromal cells collected from cPLA2{alpha}-null mice also induced the expression of COX-2 and mPGES by IL-1 and LPS, but could not produce PGE2 due to the lack of arachidonic acid release. LPS administration to wild-type mice reduced femoral bone mineral density by increased bone resorption. In cPLA2{alpha}-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2{alpha} plays a key role in PGE production by osteoblasts and in osteoclastic bone resorption, and suggest a new approach to inflammatory bone disease by inhibiting cPLA2{alpha}.

Key Words: cPLA2{alpha} • bone loss • osteoclast • osteoblast • lipopolysaccharide


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