RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression
RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression
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IL-17 介导的 JAK2/STAT3 通路通过自噬抑制增强原代成骨细胞的 RANKL 表达
DOI：
10.1080/03008207.2020.1759562
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发表时间：
2021
影响因子：
2.9
通讯作者：
Chen Lili
中科院分区：
文献类型：
--
作者：
Wang Zhongxiu;Wei Yingming;Lei Lihong;Zhong Jiahui;Shen Yeqi;Tan Jingyi;Xia Mengjiao;Wu Yanmin;Sun Weilian;Chen Lili
摘要目的：白细胞介素-17（IL-17）是由辅助性T细胞（Th）-17产生的，是一种有效的骨稳态调节剂。成骨细胞是协调炎性骨破坏和骨重建的关键细胞。本研究检测了不同浓度的IL-17对原代成骨细胞成骨和核因子-κ B配体受体激活因子（RANKL）表达的影响。方法：首先，评价原代成骨细胞的生长。其次，我们评估了IL-17对自噬水平以及相关的Janus活化激酶2（JAK 2）和下游信号转导子和转录激活子3（STAT 3）信号通路的影响。接下来，测试不同浓度的IL-17中的成骨活性。最后，使用特异性JAK 2/STAT 3信号通路抑制剂AG 490和自噬抑制剂3-MA来研究该通路和自噬在IL-17诱导的RANKL表达调节中的参与。结果：最初，我们发现IL-17处理以时间和剂量依赖性的方式促进成骨细胞的生长。接下来，我们发现低水平的IL-17促进自噬活性，而在高水平的IL-17下观察到相反的情况。此外，高水平的IL-17激活JAK 2/STAT 3信号通路，尽管这种作用通过上调自噬而逆转。此外，我们的研究结果表明，高浓度的IL-17通过激活JAK 2/STAT 3通路促进小鼠成骨细胞的分化、钙化和RANKL表达。重要的是，在高IL-17浓度下下调自噬通过抑制JAK 2/STAT 3级联进一步增强RANKL表达。结论：总体而言，我们的研究结果首次证明，IL-17通过自噬-JAK 2-STAT 3信号通路调节成骨细胞的RANKL表达，从而影响骨代谢。
ABSTRACT Objective: Interleukin-17 (IL-17), produced by T helper (Th)-17 cells, is a potent regulator of bone homeostasis. Osteoblasts are key cells that orchestrate inflammatory bone destruction and bone remodeling. This study examines the effect of different concentrations of IL-17 on osteogenesis and receptor activator of nuclear factor-kappa B ligand (RANKL) expression of primary osteoblasts. Methods: First, the growth of primary osteoblasts was evaluated. Second, we assessed the effects of IL-17 on the level of autophagy and the related Janus activated kinase 2 (JAK2) and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway. Next, osteogenic activity in different concentrations of IL-17 was tested. Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression. Results: Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner. Next, we showed that low levels of IL-17 promoted autophagy activity, whereas the opposite was observed at high levels of IL-17. Moreover, high levels of IL-17 activated the JAK2/STAT3 signaling pathway, although this effect was reversed by upregulation of autophagy. Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade. Conclusion: Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy–JAK2-STAT3 signaling pathway, thus affecting bone metabolism.