Contribution of membrane‐associated prostaglandin E<sub>2</sub> synthase to bone resorption

Saegusa, Masatomo; Murakami, Makoto; Nakatani, Yoshihito; Yamakawa, Kiyofumi; Katagiri, Mika; Matsuda, Koichi; Nakamura, Kozo; Kudo, Ichiro; Kawaguchi, Hiroshi

doi:10.1002/jcp.10356

Cited by 33 publications

(33 citation statements)

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“…7). These observations are compatible with our recent finding that mPGES-1 is induced by and mediates the effects of bone-resorptive stimuli in vitro (51). Because mPGES-1 deficiency leads to only 50% reduction of PGE 2 level in the arthritic tissue (Fig.…”

Section: Discussionsupporting

confidence: 93%

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Kamei

Yamakawa

Takegoshi

et al. 2004

Journal of Biological Chemistry

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We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE 2 -biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE 2 , but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE 2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE 2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE 2 involved in pain hypersensitivity and inflammation.

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Section: Discussionsupporting

confidence: 93%

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Kamei

Yamakawa

Takegoshi

et al. 2004

Journal of Biological Chemistry

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265

246

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“…Furthermore, PGE 2 production was diminished in gingival fibroblasts derived from mPGES-1 knockout mice, compared with wild-type fibroblasts. These results suggest that fibroblasts and smooth muscle cells are important sources of mPGES-1, which may contribute to increased PGE 2 Periodontitis is a chronic inflammatory disease involving interactions among bacterial products, host cells, and inflammatory mediators. The inflammatory response results in destruction of the tissue and alveolar bone supporting the teeth and can ultimately lead to tooth loss.…”

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confidence: 86%

“…Levels of PGE 2 are elevated in the gingival tissue and gingival fluid of patients with periodontitis, compared with periodontally healthy subjects. [2][3][4][5] It has also been reported that the inhibition of PGE 2 using selective or nonselective nonsteroidal anti-inflammatory drugs decreases periodontal disease progression and reduces alveolar bone resorption, which highlights the significance of PGE 2 in the pathogenesis of periodontal disease. 6 -8 In addition to these findings, bone resorption in lipopolysaccharide-treated mice has been shown to be dependent on PGE 2 synthesis, a finding that might be explained by the observation that PGE 2 stimulates the formation of osteoclasts.…”

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confidence: 96%

“…In gingival biopsies, positive staining for PGES was observed in fibroblasts and endothelial, smooth muscle, epithelial, and immune cells. To further explore the contribution of PGES to inflammation-induced PGE 2 production, in vitro cell culture experiments were performed using fibroblasts and endothelial, smooth muscle, and mast cells. All cell types expressed PGES and COX-2, resulting in basal levels of PGE 2 synthesis.…”

mentioning

confidence: 99%

“…16 -19 The microsomal membrane-associated and glutathione-dependent PGE synthase (mPGES-1) is induced by pro-inflammatory stimuli and involved in delayed PGE 2 synthesis. 14,17,20 The cytosolic PGE synthase (cPGES) is reported to be involved in the immediate release of PGE 2 , 21 and the glutathione-independent mPGES-2 has been reported to contribute to immediate and delayed PGE 2 synthesis but is not essential for PGE 2 synthesis. [22][23][24] The enhanced biosynthesis and role of PGE 2 in periodontal tissue have been well established, although there are currently no data about the expression of the three PGE synthases in periodontitis.…”

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confidence: 99%

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Expression of Prostaglandin E Synthases in Periodontitis

Båge

Kats

Lopez

et al. 2011

The American Journal of Pathology

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The inflammatory mediator prostaglandin E 2 (PGE 2 ) is implicated in the pathogenesis of chronic inflammatory diseases including periodontitis; it is synthesized by cyclooxygenases (COX) and the prostaglandin E synthases mPGES-1, mPGES-2, and cPGES. The distribution of PGES in gingival tissue of patients with periodontitis and the contribution of these enzymes to inflammationinduced PGE 2 synthesis in different cell types was investigated. In gingival biopsies, positive staining for PGES was observed in fibroblasts and endothelial, smooth muscle, epithelial, and immune cells. To further explore the contribution of PGES to inflammation-induced PGE 2 production, in vitro cell culture experiments were performed using fibroblasts and endothelial, smooth muscle, and mast cells. All cell types expressed PGES and COX-2, resulting in basal levels of PGE 2 synthesis. In response to tumor necrosis factor (TNF-␣), IL-1␤, and cocultured lymphocytes, however, mPGES-1 and COX-2 protein expression increased in fibroblasts and smooth muscle cells, accompanied by increased PGE 2 , whereas mPGES-2 and cPGES were unaffected. In endothelial cells, TNF-␣ increased PGE 2 production only via COX-2 expression, whereas in mast cells the cytokines did not affect PGE 2 enzyme expression or PGE 2 production. Furthermore, PGE 2 production was diminished in gingival fibroblasts derived from mPGES-1 knockout mice, compared with wild-type fibroblasts. These results suggest that fibroblasts and smooth muscle cells are important sources of mPGES-1, which may contribute to increased PGE 2 production in the inflammatory condition periodontitis.

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Microparticles stimulate the synthesis of prostaglandin E₂ via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1

Jüngel

Distler

Schulze-Horsel

et al. 2007

Arthritis & Rheumatism

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Objective. Microparticles are small vesicles that are released from activated or dying cells and that occur abundantly in the synovial fluid of patients with rheumatoid arthritis (RA). The goal of these studies was to elucidate the mechanisms by which microparticles activate synovial fibroblasts to express a proinflammatory phenotype.Methods. Microparticles from monocytes and T cells were isolated by differential centrifugation. Synovial fibroblasts were cocultured with increasing numbers of microparticles. Gene expression was analyzed by real-time polymerase chain reaction and confirmed by Western blotting and enzyme immunoassay. Arachidonic acid labeled with tritium was used to study the transport of biologically active lipids by microparticles. The roles of NF-B and activator protein 1 (AP-1) signaling were analyzed with electrophoretic mobility shift assay and transfection with small interfering RNA and IB expression vectors.Results. Microparticles strongly induced the synthesis of cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase 1 (mPGES-1), and prostaglandin E 2 (PGE 2 ). In contrast, no up-regulation of COX-1, mPGES-2, cytosolic PGES, or phospholipase A 2 was observed. The induction of PGE 2 was blocked by selective inhibition of COX-2. Microparticles activated NF-B, AP-1, p38, and JNK signaling in synovial fibroblasts. Inhibition of NF-B, AP-1, and JNK signaling reduced the stimulatory effects. Arachidonic acid was transported from leukocytes to fibroblasts by microparticles. Arachidonic acid derived from microparticles was converted to PGE 2 by synovial fibroblasts.Conclusion. These results demonstrate that microparticles up-regulate the production of PGE 2 in synovial fibroblasts by inducing COX-2 and mPGES-1. These data provide evidence for a novel mechanism by which microparticles may contribute to inflammation and pain in RA.

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Contribution of membrane‐associated prostaglandin E₂ synthase to bone resorption

Cited by 33 publications

References 59 publications

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Expression of Prostaglandin E Synthases in Periodontitis

Microparticles stimulate the synthesis of prostaglandin E₂ via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1

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Contribution of membrane‐associated prostaglandin E2 synthase to bone resorption

Cited by 33 publications

References 59 publications

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

Expression of Prostaglandin E Synthases in Periodontitis

Microparticles stimulate the synthesis of prostaglandin E2 via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1

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Contribution of membrane‐associated prostaglandin E₂ synthase to bone resorption

Microparticles stimulate the synthesis of prostaglandin E₂ via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1