Membrane-bound prostaglandin E synthase-1-mediated prostaglandin E2 production by osteoblast plays a critical role in lipopolysaccharide-induced bone loss associated with inflammation
Membrane-bound prostaglandin E synthase-1-mediated prostaglandin E2 production by osteoblast plays a critical role in lipopolysaccharide-induced bone loss associated with inflammation
复制标题
DOI：
10.4049/jimmunol.177.3.1879
复制
发表时间：
2006-08-01
影响因子：
4.4
通讯作者：
Miyaura, Chisato
中科院分区：
文献类型：
--
作者：
Inada, Masaki;Matsumoto, Chiho;Miyaura, Chisato
PGE 2在包括骨关节炎和牙周炎在内的几种疾病中充当骨吸收的有效刺激剂。三种PGE酶（PGES）被分离用于PGE 2的产生，但哪种PGES在炎性骨吸收中起主要作用仍不清楚。在这项研究中，我们使用膜结合PGES（mPGES）I缺陷小鼠（mPges 1（-/-））研究了PGE在LPS诱导的骨吸收中的作用。在野生型小鼠的成骨细胞中，在环氧合酶2和mPGES-1 mRNA表达后，LPS极大地刺激了PGE的产生，而在mPges 1（-/-）的成骨细胞中未发现PGE的产生。LPS给药降低了野生型股骨的骨体积，这与破骨细胞数量的增加有关。然而，在mPges 1（-/-）中，LPS诱导的骨丢失减少。接下来我们研究了mPGES-1缺乏是否可以改变LPS诱导的实验性牙周炎中的牙槽骨丢失。将LPS注入下牙龈，测量牙槽骨骨密度。LPS诱导野生型小鼠牙槽骨丢失，但在mPges 1（-/-）小鼠中没有，表明mPGES-1缺乏抵抗LPS诱导的牙周骨吸收。为了了解LPS诱导的成骨细胞中PGE 1产生的途径，我们使用了具有突变的tlr 4的C3 H/HeJ小鼠。来自C3 H/HeJ小鼠的成骨细胞对LPS没有反应，并且PGE 1的产生根本没有改变。C3 H/HeJ小鼠中LPS诱导的股骨骨丢失也受损。因此，LPS与成骨细胞上的TLR 4结合，直接诱导用于PGE合成的mPGES-1表达，导致随后的骨吸收。因此，mPGES-1可能为炎症性骨病的治疗提供新的靶点。
PGE2 acts as a potent stimulator of bone resorption in several disorders including osteoarthritis and periodontitis. Three PGE synthases (PGES) were isolated for PGE2 production, but which PGES has the major role in inflammatory bone resorption is still unclear. In this study, we examined the role of PGE, in LPS-induced bone resorption using membrane-bound PGES (mPGES)I-deficient mice (mPges1(-/-)). In osteoblasts from wild-type mice, PGE, production was greatly stimulated by LPS following the expression of cyclooxygenase 2 and mPGES-1 mRNA, whereas no PGE, 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, production in osteoblast, we used C3H/HeJ mice with mutated tlr4. Ostcoblasts from C3H/HeJ mice did not respond to LPS, and PGE, 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, synthesis, leading to subsequent bone resorption. Therefore, mPGES-1 may provide a new target for the treatment of inflammatory bone disease.