Kinetic analysis of synovial signalling and gene expression in animal models of arthritis.
Kinetic analysis of synovial signalling and gene expression in animal models of arthritis.
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DOI：
10.1136/ard.2009.112201
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发表时间：
2010-05
影响因子：
27.4
通讯作者：
Firestein GS
中科院分区：
文献类型：
--
作者：
Fukushima A;Boyle DL;Corr M;Firestein GS
关节炎的动物模型经常被用来评估新的治疗药物。然而，它们预测人类反应的能力是可变的。我们检测了两种关节炎模型中信号分子和基因表达的时间过程，以帮助选择模型和给药时间。研究被动K/BxN血清转移和胶原性关节炎（CIA）模型。通过Q-PCR和Western blot分析模型中不同时间点踝关节MAP激酶和ifn反应通路的激活情况。被动K/BxN和CIA的基因表达动力学和激酶磷酸化动力学有显著差异。在被动K/BxN中，所有三种MAP激酶（ERK、JNK和p38）和上游激酶在数天内被激活，除p38外，随着关节炎严重程度的降低而下降。令人惊讶的是，ifn调节的基因，包括IRF7，在模型中没有被诱导。在CIA中，ERK和JNK的激活异常低，p38磷酸化主要在疾病晚期达到峰值。ifn反应基因在CIA期间被激活，在临床关节炎发病时尤其明显。治疗时机和CIA或被动K/BxN的选择可能对治疗反应有重要影响。尤其是P38，在疾病晚期会增加。在被动K/BxN和RA中，ERK和JNK模式相似，而在CIA和RA中，ifn应答基因相似。RA与动物模型之间的二分法可以帮助解释RA疗效与临床前研究之间的相关性较差。
Animal models of arthritis are frequently used to evaluate novel therapeutic agents. However, their ability to predict responses in humans is variable. We examined the time course of signaling molecule and gene expression in two models of arthritis to assist with selection of the model and timing of drug administration. The passive K/BxN serum transfer and collagen-induced arthritis (CIA) models were studied. Activation of MAP kinase and IFN-response pathways was evaluated by Q-PCR and Western blot analysis of ankle joints at various time points during the models. The kinetics of gene expression and kinase phosphorylation were strikingly different in passive K/BxN and CIA. All three MAP kinases (ERK, JNK, and p38) and upstream kinases were activated within days in passive K/BxN and, except for p38, declined as arthritis severity decreased. Surprisingly, IFN-regulated genes, including IRF7, were not induced in the model. In CIA, activation of ERK and JNK was surprisingly low, and p38 phosphorylation mainly peaked late in disease. IFN-response genes were activated during CIA, with especially prominent peaks at the onset of clinical arthritis. Timing of treatment and selection of CIA or passive K/BxN could have an important impact on therapeutic response. p38, in particular, increases during the late stages of disease. ERK and JNK patterns are similar in passive K/BxN and RA, while IFN-response genes in CIA and RA were similar. The dichotomy between RA and animal models could help explain the poor correlation between efficacy in RA and pre-clinical studies.
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影响因子：
27.4
作者：
Corr M;Boyle DL;Ronacher L;Flores N;Firestein GS
通讯作者：
Firestein GS
影响因子：
10.5
作者：
Brancho, D;Tanaka, N;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
4.4
作者：
Shimada, T;Kawai, T;Akira, S
通讯作者：
Akira, S
炎性关节炎需要中性粒细胞的白细胞B4。
DOI：
10.1084/jem.20052371
发表时间：
2006-04-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.3
作者：
Aupperle, KR;Yamanishi, Y;Firestein, GS
通讯作者：
Firestein, GS