An essential role of cytosolic phospholipase A2alpha 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 understood. Using cytosolic phospholipase A2alpha (cPLA2alpha)-null mice, we examined the role of cPLA2alpha 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 cPLA2alpha-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 cPLA2alpha-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 cPLA2alpha-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2alpha 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 cPLA2alpha.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. tshimizu@m.u-tokyo.ac.jp
Chisato
C
Miyaura
Masaki
M
Inada
Chiho
C
Matsumoto
Tomoyasu
T
Ohshiba
Naonori
N
Uozumi
Takao
T
Shimizu
Akira
A
Ito
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000502:physiology*; D054513:Group IV Phospholipases A2; D007249:Inflammation / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism; D051193:Toll-Like Receptors
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D015232:Dinoprostone