γ-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis.
γ-Glutamyltranspeptidase is an endogenous activator of Toll-like receptor 4-mediated osteoclastogenesis.
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DOI：
10.1038/srep35930
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发表时间：
2016-10-24
影响因子：
4.6
通讯作者：
Niida S
中科院分区：
文献类型：
--
作者：
Moriwaki S;Into T;Suzuki K;Miyauchi M;Takata T;Shibayama K;Niida S
在类风湿性关节炎（RA）和牙周炎中观察到的慢性炎症相关的骨破坏是由过度的破骨细胞生成介导的。我们以前发现，γ-谷氨酰转肽酶（GGT），一种参与谷胱甘肽代谢的酶，作为这种病理性破骨细胞生成的内源性激活剂，与其酶活性无关。临床上在RA患者的关节中观察到GGT积累，并且在动物中，将重组GGT施用至龈沟作为体内牙周炎模型诱导破骨细胞数量的增加。然而，这一过程的基本机制仍不清楚。在这里，我们报告Toll样受体4（TLR 4）识别GGT激活炎症相关破骨细胞生成。与脂多糖不同，GGT对蛋白酶K处理敏感，对多粘菌素B处理不敏感。TLR 4缺乏可抑制GGT诱导的破骨细胞生成以及前体细胞中NF-κB和MAPK信号的激活此外，GGT在缺乏信号衔接子MyD 88的细胞中不诱导破骨细胞生成。在野生型小鼠中，给予牙龈沟GGT可诱导破骨细胞生成增加，但在TLR 4缺陷小鼠中不会诱导破骨细胞生成。我们的研究结果阐明了炎症相关破骨细胞生成的一种新机制，该机制涉及TLR 4识别GGT和随后激活MyD 88依赖性信号。
Chronic inflammation-associated bone destruction, which is observed in rheumatoid arthritis (RA) and periodontitis, is mediated by excessive osteoclastogenesis. We showed previously that γ-glutamyltranspeptidase (GGT), an enzyme involved in glutathione metabolism, acts as an endogenous activator of such pathological osteoclastogenesis, independent of its enzymatic activity. GGT accumulation is clinically observed in the joints of RA patients, and, in animals, the administration of recombinant GGT to the gingival sulcus as an in vivo periodontitis model induces an increase in the number of osteoclasts. However, the underlying mechanisms of this process remain unclear. Here, we report that Toll-like receptor 4 (TLR4) recognizes GGT to activate inflammation-associated osteoclastogenesis. Unlike lipopolysaccharide, GGT is sensitive to proteinase K treatment and insensitive to polymyxin B treatment. TLR4 deficiency abrogates GGT-induced osteoclastogenesis and activation of NF-κB and MAPK signaling in precursor cells. Additionally, GGT does not induce osteoclastogenesis in cells lacking the signaling adaptor MyD88. The administration of GGT to the gingival sulcus induces increased osteoclastogenesis in wild-type mice, but does not induce it in TLR4-deficient mice. Our findings elucidate a novel mechanism of inflammation-associated osteoclastogenesis, which involves TLR4 recognition of GGT and subsequent activation of MyD88-dependent signaling.
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DOI：
10.1152/ajplung.00250.2000
发表时间：
2002-10-01
影响因子：
4.9
作者：
Jean, JC;Liu, Y;Joyce-Brady, M
通讯作者：
Joyce-Brady, M
影响因子：
4.4
作者：
Itoh, K;Udagawa, N;Takahashi, N
通讯作者：
Takahashi, N
影响因子：
4.1
作者：
Jerala, Roman
通讯作者：
Jerala, Roman
影响因子：
4.2
作者：
Floch, Pauline;Pey, Vincent;Lehours, Philippe
通讯作者：
Lehours, Philippe
影响因子：
6.2
作者：
Ishizuka, Yasuyuki;Moriwaki, Sawako;Niida, Shumpei
通讯作者：
Niida, Shumpei