Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB
Decitabine represses osteoclastogenesis through inhibition of RANK and NF-κB
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地西他滨通过抑制 RANK 和 NF-kappaB 来抑制破骨细胞生成。
DOI：
10.1016/j.cellsig.2015.02.006
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发表时间：
2015-05-01
影响因子：
4.8
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Guan, Hanfeng;Mi, Baoguo;Li, Feng
DNA甲基化对于维持分化和肿瘤发生过程中基因转录的稳定抑制是必不可少的。包括地西他滨在内的去甲基化试剂可以释放抑制，导致转录程序被扰乱。最近等人和我们发现，在B细胞淋巴瘤中，地西他滨抑制B细胞特异性基因转录，激活核因子-kappaB信号，导致包括MYC在内的转位癌基因表达减少，从而抑制肿瘤细胞的增殖。在破骨细胞形成过程中，许多基因发生了DNA甲基化的变化，提示DNA甲基化在破骨细胞形成过程中起着重要作用。在目前的研究中，我们发现地西他滨抑制了破骨细胞的生成。这种抑制作用至少部分归因于地西他滨降低了包括RANK在内的多种破骨细胞特异性基因的表达。此外，地西他滨可抑制核因子-kappaB、AP-1和细胞外信号调节激酶(ERK)的活性，但不抑制PI3K/Akt信号转导通路。在体内，以去卵巢小鼠为模型，我们观察到地西他滨降低了破骨细胞活性和骨丢失。综上所述，我们的研究结果表明，地西他滨通过抑制破骨细胞特异性转录程序，包括RANK、核因子-kappaB和AP-1途径，从而抑制破骨细胞的形成。DNA甲基化可能是破骨细胞发生所必需的。地西他滨的使用可能代表着一种治疗与成骨细胞活性增加相关的疾病的新策略。(C)2015 Elsevier Inc.保留所有权利。
DNA methylation is essential for maintenance of stable repression of gene transcription during differentiation and tumorigenesis. Demethylating reagents including decitabine could release the repression, leading to perturbed transcription program. Recently others and we showed that, in B cell lymphomas, decitabine repressed B cell specific gene transcription and activated NF-kappa B signaling, causing decreased expression of translocated oncogenes including MYC and attenuated tumor cell proliferation. During osteoclastogenesis, changes in DNA methylation occurred innumerous genes, implicating important roles for DNA methylation in osteoclastogenesis. In the present study, we found that decitabine inhibited osteoclastogenesis. The inhibitory effect could be at least partially attributed to reduced expression of multiple osteoclast specific genes including RANK by decitabine. Moreover, decitabine inhibited activity of NF-kappa B, AP-1 and extracellular signal-regulated kinase (ERK), but not PI3K/Akt pathway. In vivo, using ovariectomized mouse as a model, we observed that decitabine reduced the osteoclast activity and bone loss. In conclusion, our findings demonstrated that decitabine was an inhibitor of osteoclastogenesis by repression of osteoclast specific transcription program including the RANK, NF-kappa B and AP-1 pathways. DNA methylation might be indispensable for osteoclastogenesis. The use of decitabine could represent a novel strategy in treatment of diseases associated with increased osteodast activity. (C) 2015 Elsevier Inc. All rights reserved.