Gene Expression of Osteoclast Differentiation Factor Is Induced by Lipopolysaccharide in Mouse Osteoblasts Via Toll-Like Receptors

Kikuchi, Takeshi; Matsuguchi, Tetsuya; Tsuboi, Naotake; Mitani, Akio; Tanaka, Sho; Matsuoka, Matsuzo; Yamamoto, Genta; Hishikawa, Toshimitsu; Noguchi, Toshihide; Yoshikai, Yasunobu

doi:10.4049/jimmunol.166.5.3574

Cited by 224 publications

(207 citation statements)

References 50 publications

(53 reference statements)

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“…In addition, in another experimental system, challenge with purified Aggregatibacter actinomycetemcomitans and Escherichia coli LPS also upregulated RANKL expression through the p38 MAPK pathway, in line with the present findings [33]. However, another study demonstrated that these two LPS induced RANKL expression in murine osteoblasts, mediated by the ERK MAPK pathway [34]. These discrepancies highlight the utilisation of different signalling pathways by different cell 13 types, in response to similar challenges.…”

Section: Discussionsupporting

confidence: 85%

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Reddi

Brown

Belibasakis

2011

Microbial Pathogenesis

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Periodontitis is a bacterially-induced oral inflammatory disease that is characterised by tissue degradation and bone loss. Porphyromonas gingivalis is a gram negative bacterial species highly associated with the pathogenesis of chronic periodontitis. Receptor activator of nuclear factor-kB ligand (RANKL) induces bone resorption whilst osteoprotegerin (OPG) is a decoy receptor that blocks this process. Cyclooxygenase-2 (COX-2) is an enzyme responsible for the production of prostaglandin (PGE)(2,) which is a major inflammatory mediator of bone resorption. Mitogen-activated protein kinases (MAPK) are intracellular signalling molecules involved in various cell processes, including inflammation. This study aimed to investigate the effect of P. gingivalis on MAPKs and their involvement in the regulation of RANKL, OPG and COX-2 expression in bone marrow stromal cells. P. gingivalis challenge resulted in the phosphorylation of primarily the p38 MAPK. RANKL and COX-2 mRNA expressions were upregulated, whereas OPG was down-regulated by P. gingivalis. The p38 synthetic inhibitor SB203580 abolished the P. gingivalis-induced RANKL and COX-2 expression, but did not affect OPG. Collectively, these results suggest that the p38 MAPK pathway is involved in the induction of RANKL and COX-2 by P. gingivalis, providing further insights into the pathogenic mechanisms of periodontitis. AbstractPeriodontitis is a bacterially-induced oral inflammatory disease that is characterised by tissue degradation and bone loss. Porphyromonas gingivalis is a gram negative bacterial species highly associated with the pathogenesis of chronic periodontitis. Receptor activator of nuclear factor-kB ligand (RANKL) induces bone resorption whilst osteoprotegerin (OPG) is a decoy receptor that blocks this process. Cyclooxygenase-2 (COX-2) is an enzyme responsible for the production of prostaglandin (PGE) 2, which is a major inflammatory mediator of bone resorption. Mitogen-activated protein kinases (MAPK) are intracellular signalling molecules involved in various cell processes, including inflammation. This study aimed to investigate the effect of P. gingivalis on MAPKs and their involvement in the regulation of RANKL, OPG and COX-2 expression in bone marrow stromal cells. P. gingivalis challenge resulted in the phosphorylation of primarily the p38 MAPK. RANKL and COX-2 mRNA expressions were up-regulated, whereas OPG was down-regulated by P. gingivalis. The p38 synthetic inhibitor SB203580 abolished the P. gingivalis-induced RANKL and COX-2 expression, but did not affect OPG. Collectively, these results suggest that the p38 MAPK pathway is involved in the induction of RANKL and COX-2 by P. gingivalis, providing further insights into the pathogenic mechanisms of periodontitis. KeywordsPorphyromonas gingivalis, Bone marrow stromal cells, Receptor activator of nuclear factor-kB ligand, Osteoprotegerin, Cyclooxygenase -2, p38 MAPK.3

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Section: Discussionsupporting

confidence: 85%

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Reddi

Brown

Belibasakis

2011

Microbial Pathogenesis

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“…Indeed, we found that TLR3 was expressed in E1 cells. In support of our findings, it has been reported that TLR3 mRNA was constitutively expressed in primary mouse osteoblasts (26). Our study revealed that poly(I):poly(C) up-regulated TLR3 expression in E1 cells.…”

Section: Discussionsupporting

confidence: 80%

Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells

Nakamura

Deyama²,

Yoshimura³

et al. 2007

Int J Mol Med

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Abstract. Double-stranded RNA (dsRNA) and its mimic, polyinosinic acid:polycytidylic acid [poly(I):poly(C)], are recognized by toll-like receptor 3 (TLR3) that induces the production of IFN-ß in many cell types. In the present study, we investigated the effects of poly(I):poly(C) on mouse osteoblastic MC3T3-E1 (E1) cells. Poly(I):poly(C) markedly increased IFN-ß mRNA level in a dose-dependent manner. The increase in the IFN-ß mRNA level was apparent as early as 1 h after adding poly(I):poly(C) to the culture and peaked at 12 h. Stimulation with poly(I):poly(C) enhanced the expression of CXCL10 mRNA and TLR3 in E1 cells. Moreover, poly(I):poly(C) induced tyrosine phosphorylation of the transcription factor STAT1 in E1 cells. An anti-IFN-ß neutralizing antibody partially inhibited poly(I):poly(C)-induced CXCL10 mRNA, TLR3 mRNA and STAT1 phosphorylation. These results indicate that osteoblasts secrete IFN-ß in response to viral infection and that endogenous IFN-ß induces both CXCL10 and TLR3 production via an IFN-·/ß receptor-STAT1 pathway. It is suggested that osteoblasts are involved in host defense as well as bone metabolism.

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“…This suggests that LPS induces RANKL expression by the mechanism independent of PGE 2 production. Kikuchi et al (40) reported that LPS induces RANKL through extracellular signal-regulated kinase (ERK) and PKC. We also confirmed that calcium/ PKC inhibitors, such as BAPTA-AM (an intracellular calcium chelator) and Ro-32-0432 (a PKC inhibitor), and ERK inhibitor PD98059 inhibited LPS-induced RANKL mRNA expression in osteoblasts (K.S., unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Osteoprotegerin Expression by Prostaglandin E2 Is Crucially Involved in Lipopolysaccharide-Induced Osteoclast Formation

Suda

Udagawa²,

Sato³

et al. 2004

The Journal of Immunology

149

132

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LPS is a potent stimulator of bone resorption in inflammatory diseases. The mechanism by which LPS induces osteoclastogenesis was studied in cocultures of mouse osteoblasts and bone marrow cells. LPS stimulated osteoclast formation and PGE2 production in cocultures of mouse osteoblasts and bone marrow cells, and the stimulation was completely inhibited by NS398, a cyclooxygenase-2 inhibitor. Osteoblasts, but not bone marrow cells, produced PGE2 in response to LPS. LPS-induced osteoclast formation was also inhibited by osteoprotegerin (OPG), a decoy receptor of receptor activator of NF-κB ligand (RANKL), but not by anti-mouse TNFR1 Ab or IL-1 receptor antagonist. LPS induced both stimulation of RANKL mRNA expression and inhibition of OPG mRNA expression in osteoblasts. NS398 blocked LPS-induced down-regulation of OPG mRNA expression, but not LPS-induced up-regulation of RANKL mRNA expression, suggesting that down-regulation of OPG expression by PGE2 is involved in LPS-induced osteoclast formation in the cocultures. NS398 failed to inhibit LPS-induced osteoclastogenesis in cocultures containing OPG knockout mouse-derived osteoblasts. IL-1 also stimulated PGE2 production in osteoblasts and osteoclast formation in the cocultures, and the stimulation was inhibited by NS398. As seen with LPS, NS398 failed to inhibit IL-1-induced osteoclast formation in cocultures with OPG-deficient osteoblasts. These results suggest that IL-1 as well as LPS stimulates osteoclastogenesis through two parallel events: direct enhancement of RANKL expression and suppression of OPG expression, which is mediated by PGE2 production.

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Gene Expression of Osteoclast Differentiation Factor Is Induced by Lipopolysaccharide in Mouse Osteoblasts Via Toll-Like Receptors

Cited by 224 publications

References 50 publications

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Porphyromonas gingivalis induces RANKL in bone marrow stromal cells: Involvement of the p38 MAPK

Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells

Suppression of Osteoprotegerin Expression by Prostaglandin E2 Is Crucially Involved in Lipopolysaccharide-Induced Osteoclast Formation

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