AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis
AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis
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AG490 在 RANKL 诱导的破骨细胞生成过程中抑制 NFATc1 表达和 STAT3 激活
DOI：
10.1016/j.bbrc.2013.04.084
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发表时间：
2013-06-14
影响因子：
3.1
通讯作者：
Liu, Xiang-yuan
中科院分区：
文献类型：
--
作者：
Li, Chang-hong;Zhao, Jin-xia;Liu, Xiang-yuan
通常，JAK/STAT传递细胞活化和增殖的细胞因子信号，最近的研究表明，JAK/STAT的表达升高与同种异体移植物的免疫排斥和自身免疫性疾病的炎症过程有关。然而，JAK 2/STAT 3信号传导在核因子-κ B配体受体激活因子（RANKL）介导的破骨细胞生成中的作用尚不清楚。在这项研究中，我们研究了特异性JAK 2抑制剂AG 490对体外破骨细胞分化的影响。AG 490显著抑制RANKL诱导的小鼠破骨细胞前体细胞系RAW 264.7中的破骨细胞生成。AG 490抑制细胞增殖，延迟G1向S细胞周期的转变。此外，AG 490还抑制RAW 264.7中活化T细胞核因子（NFAT）c1的表达，但不抑制c-Fos的表达。随后，我们研究了与破骨细胞生成相关的各种细胞内信号成分。AG 490对RANKL诱导的Akt、ERK 1/2活化无影响。有趣的是，AG 490部分抑制RANKL诱导的STAT 3中Ser（727）磷酸化。此外，使用siRNA下调STAT 3导致TRAP、RANK和NFATc 1表达的抑制。总之，我们证明了AG 490通过STAT 3途径抑制NFATc 1的产生和细胞增殖来抑制RANKL诱导的破骨细胞生成。这些结果表明，抑制JAK 2可能有助于治疗以破骨细胞过度生成为特征的骨疾病。(c)2013 Elsevier Inc. All rights reserved.
Commonly, JAK/STAT relays cytokine signals for cell activation and proliferation, and recent studies have shown that the elevated expression of JAK/STAT is associated with the immune rejection of allografts and the inflammatory processes of autoimmune disease. However, the role which JAK2/STAT3 signaling plays in the receptor activator of nuclear factor-kappa B ligand (RANKL)-mediated osteoclastogenesis is unknown. In this study, we investigated the effects of AG490, specific JAK2 inhibitor, on osteoclast differentiation in vitro. AG490 significantly inhibited osteoclastogenesis in murine osteoclast precursor cell line RAW264.7 induced by RANKL. AG490 suppressed cell proliferation and delayed the G1 to S cell cycle transition. Furthermore, AG490 also suppressed the expression of nuclear factor of activated T cells (NFAT) c1 but not c-Fos in RAW264.7. Subsequently, we investigated various intracellular signaling components associated with osteoclastogenesis. AG490 had no effects on RANKL-induced activation of Akt, ERK1/2. Interestingly, AG490 partly inhibited RANKL-induced phosphorylation of Ser(727) in STAT3. Additionally, down-regulation of STAT3 using siRNA resulted in suppression of TRAP, RANK and NFATc1 expression. In conclusion, we demonstrated that AG490 inhibited RANKL-induced osteoclastogenesis by suppressing NFATc1 production and cell proliferation via the STAT3 pathway. These results suggest that inhibition of JAK2 may be useful for the treatment of bone diseases characterized by excessive osteoclastogenesis. (c) 2013 Elsevier Inc. All rights reserved.