Contribution of membrane-associated prostaglandin E2 synthase to bone resorption.
This study initially confirmed that, among prostaglandins (PGs) produced in bone, only PGE(2) has the potency to stimulate osteoclastogenesis and bone resorption in the mouse coculture system of osteoblasts and bone marrow cells. For the PGE(2) biosynthesis two isoforms of the terminal and specific enzymes, membrane-associated PGE(2) synthase (mPGES) and cytosolic PGES (cPGES) have recently been identified. In cultured mouse primary osteoblasts, both mPGES and cyclooxygenase-2 were induced by the bone resorptive cytokines interleukin-1, tumor necrosis factor-alpha, and fibroblast growth factor-2. Induction of mPGES was also seen in the mouse long bone and bone marrow in vivo by intraperitoneal injection of lipopolysaccharide. In contrast, cPGES was expressed constitutively both in vitro and in vivo without being affected by these stimuli. An antisense oligonucleotide blocking mPGES expression inhibited not only PGE(2) production, but also osteoclastogenesis and bone resorption stimulated by the cytokines, which was reversed by addition of exogenous PGE(2). We therefore conclude that mPGES, which is induced by and mediates the effects of bone resorptive stimuli, may make a target molecule for the treatment of bone resorptive disorders.
Saegusa
Masatomo
M
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Murakami
Makoto
M
Nakatani
Yoshihito
Y
Yamakawa
Kiyofumi
K
Katagiri
Mika
M
Matsuda
Koichi
K
Nakamura
Kozo
K
Kudo
Ichiro
I
Kawaguchi
Hiroshi
H
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000188:drug therapy / Q000201:enzymology*; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D020319:Oligodeoxyribonucleotides, Antisense; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone