Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors.
Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors.
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DOI：
10.4049/jimmunol.0900072
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Ivashkiv LB
中科院分区：
文献类型：
--
作者：
Ji JD;Park-Min KH;Shen Z;Fajardo RJ;Goldring SR;McHugh KP;Ivashkiv LB
TLR参与促进与炎症相关的破骨细胞介导的骨吸收。TLR还激活抑制破骨细胞生成的稳态机制，并可限制与感染和炎症相关的病理性骨侵蚀的程度。我们研究了TLR抑制破骨细胞生成的机制。在人细胞培养模型中，TLR配体通过抑制NF-κB受体激活剂（RANK）的表达抑制破骨细胞生成，从而使前体细胞对RANKL的作用不敏感。在鼠细胞中观察到相似但不太稳健的RANK表达抑制。LPS抑制小鼠体内破骨细胞前体的产生，LPS吸附到骨表面导致骨吸收减少。抑制RANK表达的机制是RANK转录的下调和RANK表达所需的M-CSF信号传导的抑制。TLR通过基质金属蛋白酶和MAPK依赖性机制快速下调M-CSF受体c-Fms的细胞表面表达来抑制M-CSF信号传导。此外，TLR与IFN-γ协同抑制RANK和编码c-Fms的CSF 1 R基因的表达，并协同抑制破骨细胞生成。我们的研究结果确定了一种新的破骨细胞生成稳态调节机制，该机制靶向RANK表达并限制感染和炎症期间的骨吸收。
TLRs have been implicated in promoting osteoclast-mediated bone resorption associated with inflammatory conditions. TLRs also activate homeostatic mechanisms that suppress osteoclastogenesis and can limit the extent of pathologic bone erosion associated with infection and inflammation. We investigated mechanisms by which TLRs suppress osteoclastogenesis. In human cell culture models, TLR ligands suppressed osteoclastogenesis by inhibiting expression of receptor activator of NF-κB (RANK), thereby making precursor cells refractory to the effects of RANKL. Similar but less robust inhibition of RANK expression was observed in murine cells. LPS suppressed generation of osteoclast precursors in mice in vivo, and adsorption of LPS onto bone surfaces resulted in diminished bone resorption. Mechanisms that inhibited RANK expression were down-regulation of RANK transcription, and inhibition of M-CSF signaling that is required for RANK expression. TLRs inhibited M-CSF signaling by rapidly down-regulating cell surface expression of the M-CSF receptor c-Fms by a matrix metalloprotease- and MAPK-dependent mechanism. Additionally, TLRs cooperated with IFN-γ to inhibit expression of RANK and of the CSF1R gene that encodes c-Fms, and to synergistically inhibit osteoclastogenesis. Our findings identify a new mechanism of homeostatic regulation of osteoclastogenesis that targets RANK expression and limits bone resorption during infection and inflammation.
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DOI：
10.1084/jem.190.12.1741
发表时间：
1999-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Arai F;Miyamoto T;Ohneda O;Inada T;Sudo T;Brasel K;Miyata T;Anderson DM;Suda T
通讯作者：
Suda T
DOI：
10.4049/jimmunol.0804165
发表时间：
2009-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Park-Min KH;Ji JD;Antoniv T;Reid AC;Silver RB;Humphrey MB;Nakamura M;Ivashkiv LB
通讯作者：
Ivashkiv LB
影响因子：
4.8
作者：
Liu, Jianzhong;Wang, Shunqing;Feng, Xu
通讯作者：
Feng, Xu
影响因子：
30.8
作者：
Paloneva, J;Kestilä, M;Peltonen, L
通讯作者：
Peltonen, L
影响因子：
4.3
作者：
Bartold, PM;Marshall, RI;Haynes, DR
通讯作者：
Haynes, DR