Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation
Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation
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DOI：
10.1210/en.138.9.3666
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发表时间：
1997-09-01
期刊：
影响因子：
4.8
通讯作者：
Manolagas, SC
中科院分区：
文献类型：
--
作者：
Bellido, T;Borba, VZC;Manolagas, SC
我们先前已经证实，基质/成骨细胞共同表达共享gp130信号转导的所有细胞因子亚家族成员的受体，并且不同的受体谱系可能在该谱系的不同分化阶段表达。我们现在已经使用人(MG-63)和小鼠(MC3T3-E1)成骨细胞系以及原代小鼠颅骨细胞来验证这些受体介导细胞因子对成骨细胞生物学影响的假设。我们报道，与其他类型的细胞一样，所有的成骨细胞模型都通过激活JAK/STAT(Janus激酶/信号转导和转录激活子)和丝裂原活化蛋白激酶(MAPK)途径来响应白细胞介素6(IL-6)类型的细胞因子。此外，IL-6型细胞因子刺激碱性磷酸酶活性和骨钙素的表达，并抑制(MG-63)、刺激(M3T3-E1)或不影响(头盖骨细胞)细胞的增殖率。特定细胞类型对细胞因子家族中特定成员的反应能力严格依赖于细胞因子受体相应的配体结合亚单位(α)的存在，所有影响的大小与该亚单位的浓度密切相关。使用激酶抑制剂评估JAK/STAT和MAPK通路对细胞因子生物学效应的相对贡献。细胞因子介导的细胞增殖调节以及对碱性磷酸酶活性的刺激可被酪氨酸激酶抑制剂和苏氨酸/丝氨酸激酶抑制剂所取消，但仅受MAPK磷酸化的特异性抑制剂的最小影响。这些结果表明，IL-6型细胞因子除了具有破骨细胞的特性外，还促进定向成骨细胞向更成熟的表型分化，这一作用主要是通过激活JAK/STAT通路来实现的。
We have previously established that stromal/osteoblastic cells collectively express receptors for all members of the cytokine subfamily that share the gp130 signal transducer and that different receptor repertoires may be expressed at different stages of differentiation of this lineage. We have now used human (MG-63) and murine (MC3T3-E1) osteoblastic cell lines as well as primary murine calvaria cells to test the hypothesis that these receptors mediate effects of the cytokines on the biology of osteoblasts. We report that as in other cell types, all of the osteoblastic cell models responded to interleukin-6 (IL-6)-type cytokines with activation of both the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and the mitogen-activated protein kinase (MAPK) pathways. In addition, IL-6-type cytokines stimulated alkaline phosphatase activity and osteocalcin expression and inhibited (MG-63), stimulated (M3T3-E1), or had no effect (calvaria cells) on the rate of cell proliferation. The ability of a given cell type to respond to a particular member of this family of cytokines was strictly dependent on the presence of the corresponding ligand-binding subunit (alpha) of the cytokine receptor, and the magnitude of all the effects was closely correlated with the concentration of this subunit. The relative contribution of the JAK/STAT and MAPK pathways to the biological effects of the cytokines was evaluated using kinase inhibitors. Cytokine-mediated modulation of cell proliferation as well as stimulation of alkaline phosphatase activity were abrogated by tyrosine kinase inhibitors as well as a threonine/serine kinase inhibitor, but were only minimally affected by a specific inhibitor of MAPK phosphorylation. These results demonstrate that IL-6-type cytokines, besides their osteoclastogenic properties, promote differentiation of committed osteoblastic cells toward a more mature phenotype and that this action is mediated primarily via the activation of the JAK/STAT pathway.