Interleukin-6 inhibits receptor activator of nuclear factor κB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage:: Key role of Serine727 phosphorylation of signal transducer and activator of transcription 3
Interleukin-6 inhibits receptor activator of nuclear factor κB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage:: Key role of Serine727 phosphorylation of signal transducer and activator of transcription 3
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DOI：
10.1210/en.2007-1719
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Heymann, Dominique
中科院分区：
文献类型：
--
作者：
Duplomb, Laurence;Baud'huin, Marc;Heymann, Dominique
破骨细胞是骨吸收细胞，其在核因子κ B配体（RANKL）的受体活化剂活化后从造血前体分化。先前的研究表明，IL-6通过成骨细胞产生RANKL间接刺激破骨细胞生成。然而，很少有数据描述IL-6对破骨细胞的直接作用。为了研究这种效应，我们使用了几种模型：鼠RAW264.7细胞、小鼠骨髓和人血单核细胞。在所用的三种模型中，IL-6的加入抑制了RANKL诱导的破骨细胞生成。此外，IL-6降低破骨细胞标志物的表达和上调巨噬细胞标志物。为了阐明这种抑制，信号转导和转录激活因子（STAT）3，由IL-6激活的主要信号分子，进行了分析。添加两种STAT 3抑制剂完全消除RANKL诱导的破骨细胞生成，揭示了STAT 3的关键作用。我们证明了与酪氨酸磷酸化缺失相关的丝氨酸磷酸化STAT 3的基础水平（727）对于破骨细胞生成是必需的。此外，丝氨酸（727）磷酸化的减少导致破骨细胞分化的抑制，而IL-6刺激后酪氨酸（705）磷酸化的增加导致巨噬细胞而不是破骨细胞的形成。总之，我们首次表明IL-6通过将细胞转向巨噬细胞谱系来抑制RANKL诱导的破骨细胞生成，并证明了活化的STAT 3及其磷酸化形式在控制破骨细胞生成中的功能作用。
Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor kappa B ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT)3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine(727) associated with an absence of phosphorylation on Tyrosine(705) is essential for osteoclastogenesis. Furthermore, a decrease of Serine(727) phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine(705) phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.