α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis

Ha, Hyunil; Lee, Jong-Ho; Kim, Ha‐Neui; Kim, Hyun‐Man; Kwak, Han Bok; Lee, Seungbok; Kim, Hong-Hee; Lee, Zang Hee

doi:10.4049/jimmunol.176.1.111

Cited by 81 publications

(55 citation statements)

References 49 publications

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“…LPS-stimulated LTB 4 from primary human monocytes/macrophages (U937 macrophages did not secrete LTB 4 ) was only weakly inhibited by the ginger extract. The double inhibition of prostanoid secretion and IL-1b by ginger phenylpropanoids is interesting because IL-1b is known to reinforce PGE 2 synthesis (70), which plays multiple roles in inflammatory processes (71,72).…”

Section: Discussionmentioning

confidence: 99%

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Nievergelt

Marazzi

Schoop³

et al. 2011

The Journal of Immunology

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The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1β expression in monocytes/macrophages. Both the calcium-independent phospholipase A2 (iPLA2)-triggered maturation and the cytosolic phospholipase A2 (cPLA2)-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA2 assay, most major ginger phenylpropanoids directly inhibited i/cPLA2 from U937 macrophages, but not hog pancreas secretory phospholipase A2. The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA2 and methyl arachidonyl fluorophosphonate for cPLA2, with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially also leukotriene B4 in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA2 and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA2, the resulting attenuation of IL-1β secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.

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Section: Discussionmentioning

confidence: 99%

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Nievergelt

Marazzi

Schoop³

et al. 2011

The Journal of Immunology

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“…To generate osteoclasts, BMMs (4 ϫ 10 4 cells/well) were cultured for 4 days with M-CSF (30 ng/ml) and RANKL (100 ng/ml) in 48-well (1 ml/well) tissue culture plates. To generate osteoclasts from the coculture of primary osteoblasts and bone marrow cells, primary osteoblasts from newborn ICR mouse calvariae were prepared as described previously (Ha et al, 2006). Bone marrow cells (3 ϫ 10 5 cells/well) and primary osteoblasts (2.5 ϫ 10 4 cells/well) were cocultured for 6 to 7 days in 1 ml of ␣-MEM complete medium in 48-well tissue culture plates.…”

Section: Methodsmentioning

confidence: 99%

“…An IL-1-induced mouse calvarial bone loss model was used as described previously (Ha et al, 2006). In brief, a collagen sponge treated with vehicle (PBS) or IL-1 (2 g) was implanted over calvarial bone in groups of 10 mice (6-weekold male ICR mice).…”

Section: Methodsmentioning

confidence: 99%

Epigallocatechin-3-gallate Inhibits Osteoclastogenesis by Down-Regulating c-Fos Expression and Suppressing the Nuclear Factor-κB Signal

Lee

Hexiu²,

Shim³

et al. 2009

Mol Pharmacol

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125

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Epigallocatechin-3-gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast differentiation. However, the precise molecular mechanisms underlying the inhibitory action of EGCG in osteoclastogenesis and the effect of EGCG on inflammation-mediated bone destruction remain unclear. In this study, we found that EGCG inhibited osteoclast formation induced by osteoclastogenic factors in bone marrow cell-osteoblast cocultures but did not affect the ratio of receptor activator of nuclear factor B (NF-B) ligand (RANKL) to osteoprotegerin induced by osteoclastogenic factors in osteoblasts. We also found that EGCG inhibited osteoclast formation from bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor plus RANKL in a dose-dependent manner without cytotoxicity. Pretreatment with EGCG significantly inhibited RANKL-induced the gene expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. EGCG suppressed RANKL-induced activation of c-Jun N-terminal protein kinase (JNK) pathway, among the three well known mitogen-activated protein kinases and also inhibited RANKL-induced phosphorylation of the NF-B p65 subunit at Ser276 and NF-B transcriptional activity without affecting the degradation of IB␣ and NF-B DNA-binding in BMMs. The inhibitory effect of EGCG on osteoclast formation was somewhat reversed by retroviral c-Fos overexpression, suggesting that c-Fos is a downstream target for antiosteoclastogenic action of EGCG. In addition, EGCG treatment reduced interleukin-1-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo. Taken together, our data suggest that EGCG has an antiosteoclastogenic effect by inhibiting RANKL-induced the activation of JNK/c-Jun and NF-B pathways, thereby suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.Bone mass homeostasis is regulated by the coupled actions of bone-forming osteoblasts and bone-resorbing osteoclasts, a process termed remodeling. Many pathological and osteopenic diseases, including postmenopausal osteoporosis, lytic bone metastasis, rheumatoid arthritis, periodontitis, and Paget's disease, are characterized by progressive and excessive bone resorption by osteoclasts, which are multinucleated cells derived from the monocyte/ macrophage linage precursors (Boyle et al., 2003). Macrophage colony-stimulating factor (M-CSF), which is produced by osteoblasts, plays an important role in proliferation and subsequent osteoclast differentiation in mouse bone marrow cultures (Biskobing et al., 1995). A tumor necrosis factor (TNF) family member, receptor activator of nuclear factor B (NF-B) ligand (RANKL), is

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“…Histological sections (5 mm) were prepared, stained for TRAP, and counterstained using methyl green (0.5% [pH 4]). To study the effects of MK886 on LPS-induced bone loss in vivo, bone loss was induced by LPS administration using previously described methods (18), with a slight modification. Mice received i.p.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

5-Lipoxygenase Mediates RANKL-Induced Osteoclast Formation via the Cysteinyl Leukotriene Receptor 1

Lee

Park

Noh

et al. 2012

The Journal of Immunology

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5-Lipoxygenase (5-LO) catalyzes the formation of two major groups of leukotrienes, leukotriene B4 and cysteinyl leukotrienes (CysLTs), and it has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in osteoclastogenesis has not been investigated. In this study, we used mouse bone marrow–derived macrophages (BMMs) to show that 5-LO inhibitor suppresses RANKL-induced osteoclast formation. Inhibition of 5-LO was associated with impaired activation of multiple signaling events downstream of RANK, including ERK and p38 phosphorylation, and IκB degradation, followed by a decrease in NFATc1 expression. Ectopic overexpression of a constitutively active form of NFATc1 partly rescued the antiosteoclastogenic effect of 5-LO inhibitor. The knockdown of 5-LO in BMMs also resulted in a significant reduction in RANKL-induced osteoclast formation, accompanied by decreased expression of NFATc1. Similar effects were shown with CysLT receptor (CysLTR)1/2 antagonist and small RNA for CysLTR1 in BMMs, indicating the involvement of CysLT and CysLTR1 in 5-LO–mediated osteoclastogenesis. Finally, 5-LO inhibitor suppressed LPS-induced osteoclast formation and bone loss in the in vivo mouse experiments, suggesting a potential therapeutic strategy for treating diseases involving bone destruction. Taken together, the results of this study demonstrate that 5-LO is a key mediator of RANKL-induced osteoclast formation and possibly a novel therapeutic target for bone-resorption diseases.

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α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis

Cited by 81 publications

References 49 publications

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Epigallocatechin-3-gallate Inhibits Osteoclastogenesis by Down-Regulating c-Fos Expression and Suppressing the Nuclear Factor-κB Signal

5-Lipoxygenase Mediates RANKL-Induced Osteoclast Formation via the Cysteinyl Leukotriene Receptor 1

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