Cot/Tpl2 is Essential for RANKL Induction by Lipid A in Osteoblasts

Kikuchi, Takeshi; Yoshikai, Yasunobu; Miyoshi, Jun; Katsuki, Motoya; Musikacharoen, Tipayaratn; Mitani, Akio; Tanaka, Sho; Noguchi, Toshihide; Matsuguchi, Tetsuya

doi:10.1177/154405910308200712

Cited by 24 publications

(22 citation statements)

References 28 publications

(43 reference statements)

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“…The data further suggest that LPS mediates bone resorption by both IFN-γ-dependent and IFN-γ-independent pathways, although the independent pathway appears to be dominant. This interpretation is consistent with studies reporting that LPS induces osteoclast formation by multiple mechanisms, including direct stimulation of RANKL expression in osteoblasts (47); production of TNF-α, IL-1, and IL-6 by macrophages; and stimulation of osteoclast survival (48). Our data suggest that these proresorptive effects are further amplified by IFN-γ-mediated pathways.…”

Section: Discussionsupporting

confidence: 81%

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Gao¹,

Grassi²,

Ryan³

et al. 2007

J. Clin. Invest.

405

388

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T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-γ is a major product of activated T helper cells that can function as a pro-or antiresorptive cytokine, but the reason why IFN-γ has variable effects in bone is unknown. Here we show that IFN-γ blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-α. Analysis of the in vivo effects of IFN-γ in 3 mouse models of bone loss -ovariectomy, LPS injection, and inflammation via silencing of TGF-β signaling in T cells -reveals that the net effect of IFN-γ in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-γ has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-γ signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.

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Section: Discussionsupporting

confidence: 81%

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Gao¹,

Grassi²,

Ryan³

et al. 2007

J. Clin. Invest.

405

388

View full text Add to dashboard Cite

show abstract

“…TPL2 is a protooncogene that is overexpressed in various cancer types, including breast cancer, gastric cancer, colonic adenocarcinomas, Epstein-Barr virus-related Hodgkin lymphomas, and nasopharyngeal carcinomas (Sourvinos et al, 1999;Kikuchi et al, 2003;Christoforidou et al, 2004;Clark et al, 2004). Moreover, TPL2 is required for epidermal growth factor-induced neoplastic transformation, and TPL2 overexpression promotes the proliferation and transformation of mouse embryonic fibroblasts (Chiariello et al, 2000;Choi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells

Kim

Son²,

Jang³

et al. 2011

J Pharmacol Exp Ther

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Targeting tumor necrosis factor (TNF)-␣-mediated signal pathways may be a promising strategy for developing chemopreventive agents, because TNF-␣-mediated cyclooxygenase (COX)-2 expression plays a key role in inflammation and carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] exerts anticarcinogenic effects, although little is known about the underlying molecular mechanisms and specific targets of this compound. In the present study, we found that luteolin inhibited TNF-␣-induced COX-2 expression by down-regulating the transactivation of nuclear factor-B and activator protein-1. Furthermore, luteolin inhibited TNF-␣-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/ERK/p90 RSK , mitogen-activated protein kinase kinase 4/c-Jun N-terminal kinase/ c-Jun, and Akt/p70 S6K . However, it had no effect on the phosphorylation of p38. These effects of luteolin on TNF-␣-mediated signaling pathways and COX-2 expression are similar to those achieved by blocking tumor progression locus 2 serine/ threonine kinase (TPL2) using pharmacologic inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro and in TPL2 immunoprecipitation kinase assays by binding directly in an ATP-competitive manner. Overall, these results indicate that luteolin exerts potent chemopreventive activities, which primarily target TPL2.

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“…LPS can stimulate the expression of IL-1ß, TNF-α, IL-6, and RANKL by activating the innate immune response (Nakashima et al, 2000;Jiang et al, 2002;Kikuchi et al, 2003). Within periodontal tissues, TLR-2 and -4 expression is increased in severe disease states, suggesting that these receptors have an increased capacity to signal and influence downstream cytokine expression (Mori et al, 2003).…”

mentioning

confidence: 99%

MAP Kinase Phosphatase-1 Protects against Inflammatory Bone Loss

Sartori

Kirkwood

2009

J Dent Res

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The mitogen-activated protein (MAP) kinase phosphatase (MKP) family plays an important function in regulating the pro-inflammatory cytokines by deactivating MAP kinases. MKP-1 is essential for the dephosphorylation of p38 MAP kinase that regulates expression of IL-6, TNF-α, and IL-1β. We hypothesized that MKP-1 regulates inflammatory bone loss in experimental periodontitis. Wild-type and Mkp-1 -/-mice received A. actinomycetemcomitans LPS injection in the palatal region or PBS control 3 times/wk for 30 days. Mice were killed, and maxillae were assessed by microcomputed tomography, histological analysis, and TRAP staining for measurement of bone loss, extent of inflammation, and degree of osteoclastogenesis. Results indicated that, in LPSinjected Mkp-1

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Cot/Tpl2 is Essential for RANKL Induction by Lipid A in Osteoblasts

Cited by 24 publications

References 28 publications

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Luteolin, a Novel Natural Inhibitor of Tumor Progression Locus 2 Serine/Threonine Kinase, Inhibits Tumor Necrosis Factor-α-Induced Cyclooxygenase-2 Expression in JB6 Mouse Epidermis Cells

MAP Kinase Phosphatase-1 Protects against Inflammatory Bone Loss

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