An Essential Role of Cytosolic Phospholipase A2 (cid:2) in Prostaglandin E2–mediated Bone Resorption Associated with Inflammation

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 un-derstood. Using cytosolic phospholipase A2 (cid:2) (cPLA2 (cid:2) )-null mice, we examined the role of cPLA2 (cid:2) 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 (cid:2) -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 (cid:2) 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 (cid:2) -null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2 (cid:2) 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 (cid:2) .

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