Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-κB pathways
Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-κB pathways
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DOI：
10.1016/j.intimp.2018.03.021
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发表时间：
2018-05-01
影响因子：
5.6
通讯作者：
Liu, Xiang-yuan
中科院分区：
文献类型：
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作者：
Li, Chang-hong;Xu, Lin-lin;Liu, Xiang-yuan
托法替尼是一种小分子JAK抑制剂，已被广泛用于减轻炎症和抑制类风湿性关节炎中骨破坏的进展。STAT 3是JAK的下游信号分子，在响应炎症细胞因子的信号激活中发挥关键作用。因此，靶向STAT 3可能是治疗破骨细胞相关疾病（如类风湿性关节炎）的一种鼓舞人心的策略。在这项研究中，我们首先研究了STAT 3抑制剂Stattic对NF-κ B B配体受体激活剂（RANKL）介导的破骨细胞生成的影响。Stattic以剂量依赖性方式抑制RANKL诱导的RAW264.7细胞中的破骨细胞分化和骨吸收。Stattic还抑制RAW264.7细胞中RANKL诱导的破骨细胞相关基因抗酒石酸酸性磷酸酶、基质金属蛋白酶9、组织蛋白酶K、RANK、肿瘤坏死因子受体相关因子6和破骨细胞相关受体的上调。此外，Stattic在较高剂量下对细胞增殖和细胞周期进程表现出抑制作用。在分子水平上，Stattic抑制RANKL诱导的STAT 3和NF-κ B通路的激活，而不显著影响MAPK信号传导。此外，Stattic抑制RANKL诱导的破骨细胞相关转录因子c-Fos和NFATc 1的表达。重要的是，Stattic还可以防止卵巢切除术引起的骨质流失。总之，我们的数据证实Stattic通过干扰RANKL诱导的STAT 3和NF-κ B信号传导来限制破骨细胞生成和骨丢失。因此，Stattic代表了一种新型的破骨细胞抑制剂，可用于骨质疏松症和类风湿性关节炎等疾病。
Tofacitinib, a small molecule JAK inhibitor, has been widely used to reduce inflammation and inhibit progression of bone destruction in rheumatoid arthritis. STAT3, a downstream signaling molecule of JAK, plays a key role in the activation of signaling in response to inflammatory cytokines. Thus, targeting STAT3 may be an inspiring strategy for treating osteoclast-related diseases such as rheumatoid arthritis. In this study, we first investigated the effects of Stattic, a STAT3 inhibitor, on receptor activator of NF-kappa B ligand (RANKL)-mediated osteoclastogenesis. Stattic inhibited osteoclast differentiation and bone resorption in RANKL-induced RAW264.7 cells in a dose-dependent manner. Stattic also suppressed RANKL-induced upregulation of osteoclast-related genes tartrate-resistant acid phosphatase, matrix metalloproteinase 9, cathepsin K, RANK, tumor necrosis factor receptor-associated factor 6, and osteoclast-associated receptor in RAW264.7 cells. Moreover, Stattic exhibited an inhibitory effect on cell proliferation and cell cycle progression at higher dosages. At the molecular level, Stattic inhibited RANKL-induced activation of STAT3 and NF-kappa B pathways, without significantly affecting MAPK signaling. In addition, Stattic inhibited RANKL-induced expression of osteoclast-related transcription factors c-Fos and NFATc1. Importantly, Stattic also prevented bone loss caused by ovariectomy. Together, our data confirm that Stattic restricts osteoclastogenesis and bone loss by disturbing RANKL-induced STAT3 and NF-kappa B signaling. Thus, Stattic represents a novel type of osteoclast inhibitor that could be useful for conditions such as osteoporosis and rheumatoid arthritis.