21st July 06:01
Role of excessive PGE2 in TLR4-induced bone loss (periodontitis osteoarthritis)
J Immunol. 2006 Aug 1;177(3):1879-85.
Membrane-bound prostaglandin E synthase-1-mediated prostaglandin E2
production by osteoblast plays a critical role in
lipopolysaccharide-induced bone loss associated with inflammation.
Inada M, Matsumoto C, Uematsu S, Akira S, Miyaura C.
Department of Biotechnology and Life Science, Tokyo University of
Agriculture and Technology, Tokyo, Japan.
PGE(2) acts as a potent stimulator of bone resorption in several
disorders including osteoarthritis and periodontitis. Three PGE
synthases (PGES) were isolated for PGE(2) production, but which PGES has
the major role in inflammatory bone resorption is still unclear. In this
study, we examined the role of PGE(2) in LPS-induced bone resorption
using membrane-bound PGES (mPGES)-1-deficient mice (mPges1(-/-)). In
osteoblasts from wild-type mice, PGE(2) production was greatly
stimulated by LPS following the expression of cyclooxygenase 2 and
mPGES-1 mRNA, whereas no PGE(2) production was found in osteoblasts from
mPges1(-/-). LPS administration reduced the bone volume in wild-type
femur that was associated with an increased number of osteoclasts. In
mPges1(-/-), however, LPS-induced bone loss was reduced. We next
examined whether mPGES-1 deficiency could alter the alveolar bone loss
in LPS-induced experimental periodontitis. LPS was injected into the
lower gingiva and bone mineral density of alveolar bone was measured.
LPS induced the loss of alveolar bone in wild-type, but not in
mPges1(-/-) mice, suggesting an mPGES-1 deficiency resistant to
LPS-induced periodontal bone resorption. To understand the pathway of
LPS-induced PGE(2) production in osteoblast, we used C3H/HeJ mice with
mutated tlr4. Osteoblasts from C3H/HeJ mice did not respond to LPS, and
PGE(2) production was not altered at all. LPS-induced bone loss in the
femur was also impaired in C3H/HeJ mice. Thus, LPS binds to TLR4 on
osteoblasts that directly induce mPGES-1 expression for PGE(2)
synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may
provide a new target for the treatment of inflammatory bone disease.