TLR2-dependent Modulation of Osteoclastogenesis by Porphyromonas gingivalis through Differential Induction of NFATc1 and NF-κB

被引:81
|
作者
Zhang, Ping [1 ]
Liu, Jianzhong
Xu, Qingan [2 ,3 ]
Harber, Gregory
Feng, Xu
Michalek, Suzanne M.
Katz, Jenny [1 ]
机构
[1] Univ Alabama Birmingham, Dept Pediat Dent, Birmingham, AL 35294 USA
[2] Wuhan Univ, Key Lab Oral Biomed Engn, Sch Stomatol, Minist Educ, Wuhan 430079, Hubei, Peoples R China
[3] Wuhan Univ, Key Lab Oral Biomed Engn, Hosp Stomatol, Minist Educ, Wuhan 430079, Hubei, Peoples R China
关键词
TOLL-LIKE RECEPTORS; PERIODONTAL-DISEASE; BONE LOSS; CYTOKINE PRODUCTION; SIGNALING PATHWAY; LIPOPOLYSACCHARIDE; EXPRESSION; RANKL; OSTEOIMMUNOLOGY; INHIBITION;
D O I
10.1074/jbc.M110.198085
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Osteolytic diseases, including rheumatoid arthritis, osteomyelitis, and periodontitis, are usually associated with bacterial infections. However, the precise mechanisms by which bacteria induce bone loss still remain unclear. Evidence exists that Toll-like receptor (TLR) signaling regulates both inflammation and bone metabolism and that the receptor activator of NF-kappa B ligand (RANKL) and its receptor RANK are the key regulators for bone remodeling and for the activation of osteoclasts. Here, we investigate the direct effects of the periodontal pathogen Porphyromonas gingivalis on osteoclast differentiation and show that P. gingivalis differentially modulates RANKL-induced osteoclast formation contingent on the state of differentiation of osteoclast precursors. In addition, although an optimal induction of cytokines by P. gingivalis is dependent on TLR2 and TLR4, as well as myeloid differentiation factor 88 and Toll/IL-1R domain-containing adaptor-inducing IFN-beta, P. gingivalis utilizes TLR2/ myeloid differentiation factor 88 in modulating osteoclast differentiation. P. gingivalis modulates RANKL-induced osteoclast formation by differential induction of NFATc1 and c-Fos. More importantly, RANKL-mediated lineage commitment also has an impact on P. gingivalis-induced cytokine production. RANKL inhibits P. gingivalis-induced cytokine production by down-regulation of TLR/NF-kappa B and up-regulation of NFATc1. Our findings reveal novel aspects of the interactions between TLR and RANK signaling and provide a new model for understanding the mechanism underlying the pathogenesis of bacteria-mediated bone loss.
引用
收藏
页码:24159 / 24169
页数:11
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