The Role of MAP Kinase in The Signal Transduction Pathways Activated by Mechanical Stress in Mesenchymal Cells.

MAP 激酶在间充质细胞机械应力激活的信号转导途径中的作用。

• 批准号: 09672094
• 负责人: MORIYAMA Keiji
• 金额: $ 2.05万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672094/
• 关键词: mechanical stress; IL-6; soluble IL-6receptor; gp130; MAP kinase; JAK-STAT; osteoblast; メカニカメストレス; 歯根膜細胞; 力学的刺激; チロシンリン酸化; src

Studies on interleukin-6 (IL-6) in bone metabolism in response to mechanical stress have been accumulating. However, its effects on osteoblasts are still unclear because the results are conflicting depending on the study models employed. We reasoned that these conflicting data are due to variable expression levels of membrane-bound IL-6 receptors (IL-6Rs). In the present study, we found that IL-6 in combination with soluble IL-6R (sIL-6R) consistently caused a marked elevation of alkaline phosphatase and a decrease in proliferation in the human osteoblastic cell line MG-63, which expressed no detectable membrane-bound IL-6R and failed to respond to IL-6. These effects of IL-6/sIL-6R were blocked by neutralizing antibodies to the IL-6 signal transducer gp 130, suggesting an involvement of IL-6 signaling in the elicitation of the effects of IL-6/sIL6R.Upon stimulation with IL-6/sIL-6R, the gp 130, cytoplasmic Janus kinases JAK1 and JAK2 were tyrosine phosphorylated. Moreover, signal transducers and activators of transcription STAT1 and STAT3 were also tyrosine phosphorylated, translocated to the nucleus, and bound to the putative STAT-binding DNA elements. In addition, mitogen-activated protein (MAP) kinase was also activated in response to IL-6/sIL-6R.These data demonstrate that sIL-SR may enhance the responsiveness of MG-63 cells to IL-6. Thus, IL-6 in collaboration with sIL-6R may modulate differentiation and proliferation of osteoblastic cells, presumably by activating two distinct signaling pathways of JAK-STAT and MAP kinase.

关于白介素6(IL-6)在机械应力下骨代谢中的作用的研究已经积累起来。然而，它对成骨细胞的影响仍然不清楚，因为根据所采用的研究模型，结果是相互矛盾的。我们推测，这些相互矛盾的数据是由于膜结合的IL-6受体(IL-6Rs)的表达水平不同所致。在本研究中，我们发现IL-6与可溶性IL-6R(sIL-6R)联合应用能显著提高人成骨细胞系MG-63的碱性磷酸酶活性，抑制其增殖。MG-63不表达膜结合型IL-6R，对IL-6无反应。IL-6/sIL-6R的这些作用可被IL-6信号转导通路GP 130的中和性抗体阻断，提示IL-6信号转导通路参与了IL-6/sIL-6R效应的诱导。在IL-6/sIL-6R的刺激下，GP 130、胞浆Janus激酶JAK1和JAK2被酪氨酸磷酸化。此外，信号转导和转录激活因子STAT1和STAT3也被酪氨酸磷酸化，移位到细胞核，并与假定的STAT结合的DNA元件结合。此外，IL-6/sIL-6R还激活了丝裂原活化蛋白(MAP)激酶。这些数据表明sIL-SR可能增强MG-63细胞对IL-6的反应性。因此，IL-6与sIL-6R协同作用可能通过激活JAK-STAT和MAP激酶两条不同的信号通路来调控成骨细胞的分化和增殖。

项目成果

R.Nishimura et al.: "Combination of Interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-Stat and MAP kinase pathways in MG-63 human osteoblastic osteosarcoma cells." J.Bone and Mineral Res.13・5. 777-785 (1998)

R. Nishimura 等人：“白细胞介素 6 和可溶性白细胞介素 6 受体的组合可诱导 MG-63 人成骨细胞骨肉瘤细胞中 JAK-Stat 和 MAP 激酶途径的分化和激活，J.Bone and Mineral Res.13・” 5.777-785（1998）

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K.MOriyama et al.: "Transactions,8th international Congress on Cleft Palate and Related Craniofacial Anomalies" S.T.Lee, Stamford Press Pte Ltd,Singapore, 1066 (1997)

K.MOriyama 等人：“第 8 届国际腭裂及相关颅面异常大会交易”S.T.Lee，Stamford Press Pte Ltd，新加坡，1066 (1997)