Interactions between the genes that regulate the body clock and those that worsen rheumatoid arthritis
Interactions between the genes that regulate the body clock and those that worsen rheumatoid arthritis
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调节生物钟的基因与导致类风湿性关节炎恶化的基因之间的相互作用
DOI：
10.1586/eci.10.3
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发表时间：
2010
影响因子：
4.4
通讯作者：
A. Hashiramoto
中科院分区：
文献类型：
--
作者：
S. Shiozawa;A. Hashiramoto
类风湿性关节炎(RA)仍然是一种难治的疾病。类风湿关节炎的病理特征首先是滑膜组织过度生长。类风湿滑膜过度生长一直被认为是“肿瘤样”[1，2]，但其原因尚不清楚。2001年，Kawasaki et al.偶然发现在RA[3，4]中，Wee1激酶在c-Fos/AP-1过表达后上调。C-Fos/AP-1的过度表达导致滑膜过度生长和类风湿关节炎典型的骨质疏松[5，6]，反之亦然，选择性抑制c-Fos/AP-1可以解决关节炎[7]。其原因是，编码炎性细胞因子，包括肿瘤坏死因子-a、白介素1b和白介素6，以及基质降解基质金属蛋白酶的基因都受到c-Fos/AP-1[7]的直接控制。我们的研究还表明，Wee1激酶在细胞周期的M期通过磷酸化CDC2的Tyr15来抑制有丝分裂细胞的分裂，也受c-Fos/AP-1[3]的直接控制。因此，在RA中c-Fos/AP-1上调后Wee1激酶上调[4]，类风湿滑膜细胞不能分裂，一方面是因为Wee1升高，另一方面是由于RA中c-Fos/AP-1上调而导致的增殖增加。因此，类瘤性滑膜过度生长是由于RA中c-Fos/AP-1和Wee1激酶表达增加所致。类风湿性关节炎的另一个重要特征是疾病的昼夜节律表现，如晨僵，这也包括在类风湿性关节炎的诊断标准中。患者的身体状况、关节炎、握力和主观疼痛在清晨都较差，到了晚上变得轻微[8]。体征和症状的昼夜周期变化在早晨达到高峰，其原因机制仍有待阐明，特别是与调节生物钟的基因表达有关。Hashiramoto等人。Shiozawa和Shiozawa研究了调节生物钟的基因和那些加重关节炎的基因之间的分子相互作用，现在表明关节炎可以显著干扰宿主生物钟的昼夜节律；反之亦然，生物钟调节关节炎[9]。特别是，虽然哺乳动物的时钟基因Period和CryptoChrome(Cry)调节昼夜节律，但我们发现在实验性关节炎小鼠模型中，炎症滑膜细胞和脾细胞的昼夜节律性和Period的节律性表达明显受到干扰(图1)。其他时钟基因BMal1和DBP的表达也在关节炎诱导下在脾细胞中受到干扰。另一方面，Cry1和Cry2基因的缺失导致活化的CD3CD69T细胞数量增加，脾组织产生更多的肿瘤坏死因子-α。当关节炎被诱导时，Cry1Cry2小鼠出现关节肿胀的最大加剧和关节炎基本介质的上调，Shunichi Shiozawa
Rheumatoid arthritis (RA) still remains an intractable disease. The pathological feature characterizing RA is, in the first instance, the overgrowth of synovial tissue. The overgrowth of rheumatoid synovium has long been considered as ‘tumor-like’ [1,2], while its cause has remained unclear. In 2001, Kawasaki et al. happened to find that Wee1 kinase was upregulated subsequent to the overexpression of c-Fos/AP-1 in RA [3,4]. The overexpression of c-Fos/AP-1 causes synovial overgrowth and osteoporosis typical of RA [5,6] and, vice versa, selective inhibition of c-Fos/AP-1 resolves arthritis [7]. The reason for this is the fact that genes encoding both inflammatory cytokines, including TNF-a, IL-1b and IL-6, and matrix-degrading matrix metalloproteinases are under the direct control of c-Fos/AP-1 [7]. Our studies also show that Wee1 kinase, which inhibits mitotic cell division by phosphorylating Tyr15 of CDC2 during the M phase of the cell cycle, is also under the direct control of c-Fos/ AP-1 [3]. It then follows that Wee1 kinase is upregulated subsequent to the upregulation of c-Fos/AP-1 in RA [4], and that rheumatoid synovial cells cannot divide because of elevated Wee1 on the one hand, and in the face of increased proliferation as a result of upregulated c-Fos/AP-1 in RA on the other hand. Consequently, the tumor-like synovial overgrowth is due to the increase in both c-Fos/AP-1 and Wee1 kinase in RA. Another important feature of RA is the circadian manifestation of the disease, such as morning stiffness, which is also included in the diagnostic criteria of RA. The patient’s physical condition, arthritis, grip strength and subjective pain are all worse in the early morning and become mild in the evening [8]. The causal mechanisms underlying this diurnal cycle of changes in signs and symptoms reaching peak levels in the morning remain to be clarified, especially in relation to the gene expression that regulates the body clock. Hashiramoto et al. and Shiozawa have investigated the molecular interactions between the genes that regulate the body clock and those that worsen arthritis, and now show that arthritis can significantly disturb the circadian rhythmicity of the host’s clock; and, vice versa, that the circadian clock modulates arthritis [9]. In particular, while the mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm, we show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are significantly disturbed in mouse models of experimental arthritis (Figure 1). The expression of other clock genes, Bmal1 and Dbp, was also disturbed in spleen cells by arthritis induction. On the other hand, deletion of Cry1 and Cry2 resulted in an increase in the number of activated CD3 CD69 T cells and a higher production of TNF-a from the spleen. When arthritis is induced, Cry1Cry2 mice develop maximal exacerbation of joint swelling and upregulation of essential mediators of arthritis, Shunichi Shiozawa
影响因子：
56.9
作者：
Matsuo, T;Yamaguchi, S;Okamura, H
通讯作者：
Okamura, H
影响因子：
4.4
作者：
Hashiramoto, Akira;Yamane, Takashi;Shiozawa, Shunichi
通讯作者：
Shiozawa, Shunichi