Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways.
Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways.
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IL-6 和 sIL-6R 的组合通过 NF-kappa B、ERK 和 JNK 信号通路差异调节不同水平的 RANKL 诱导的破骨细胞生成
DOI：
10.1038/srep41411
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发表时间：
2017-01-27
影响因子：
4.6
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Feng W;Liu H;Luo T;Liu D;Du J;Sun J;Wang W;Han X;Yang K;Guo J;Amizuka N;Li M
已知白细胞介素(IL)-6通过促进成骨细胞/基质细胞产生核因子κ b配体受体激活剂（RANKL）间接促进破骨细胞的形成。然而，关于IL-6对破骨细胞发生的直接作用知之甚少。在此，我们在体外测定了IL-6及其可溶性受体（sIL-6R）对rankl诱导的破骨细胞前体形成的直接影响。我们发现IL-6/sIL-6R分别显著促进和抑制低（10 ng/ml）和高（50 ng/ml） RANKL诱导的破骨细胞分化。通过骨吸收坑形成实验，破骨细胞标记基因和转录因子的表达证实了IL-6/sIL-6R对rankl诱导的破骨细胞形成的差异调控。细胞内信号转导分析显示，IL-6/sIL-6R分别特异性上调和下调低水平RANKL诱导的NF-κB（活化B细胞的核因子κ轻链增强子）、ERK（细胞外信号调节激酶）和JNK （c-Jun n-末端激酶）的磷酸化。综上所述，我们的研究结果表明，IL-6/sIL-6R通过调节NF-κB、ERK和JNK信号通路，对rankl诱导的破骨细胞分化和活性有差异调节。因此，IL-6可能在破骨细胞形成中发挥双重作用，要么作为促吸收因子，要么作为骨的保护者，这取决于局部微环境中RANKL的水平。
Interleukin (IL)-6 is known to indirectly enhance osteoclast formation by promoting receptor activator of nuclear factor kappa-B ligand (RANKL) production by osteoblastic/stromal cells. However, little is known about the direct effect of IL-6 on osteoclastogenesis. Here, we determined the direct effects of IL-6 and its soluble receptor (sIL-6R) on RANKL-induced osteoclast formation by osteoclast precursors in vitro. We found IL-6/sIL-6R significantly promoted and suppressed osteoclast differentiation induced by low- (10 ng/ml) and high-level (50 ng/ml) RANKL, respectively. Using a bone resorption pit formation assay, expression of osteoclastic marker genes and transcription factors confirmed differential regulation of RANKL-induced osteoclastogenesis by IL-6/sIL-6R. Intracellular signaling transduction analysis revealed IL-6/sIL-6R specifically upregulated and downregulated the phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), ERK (extracellular signal–regulated kinase) and JNK (c-Jun N-terminal kinase) induced by low- and high level RANKL, respectively. Taken together, our findings demonstrate that IL-6/sIL-6R differentially regulate RANKL-induced osteoclast differentiation and activity through modulation of NF-κB, ERK and JNK signaling pathways. Thus, IL-6 likely plays a dual role in osteoclastogenesis either as a pro-resorption factor or as a protector of bone, depending on the level of RANKL within the local microenvironment.