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

白细胞介素-6（IL-6）在机械应力下骨代谢中的作用研究日益增多。然而，其对成骨细胞的影响仍然不清楚，因为结果是相互矛盾的，这取决于所采用的研究模型。我们推断这些相互矛盾的数据是由于膜结合IL-6受体（IL-6 Rs）的表达水平不同。在本研究中，我们发现，IL-6与可溶性IL-6 R（sIL-6 R）的组合始终引起碱性磷酸酶的显着升高和人成骨细胞系MG-63，其中表达没有检测到的膜结合IL-6 R，未能响应IL-6的增殖减少。IL-6/sIL-6 R的这些作用可被IL-6信号转导蛋白gp 130的中和抗体阻断，提示IL-6信号转导参与了IL-6/sIL-6 R的作用。此外，信号转导子和转录激活子STAT 1和STAT 3也被酪氨酸磷酸化，易位到细胞核，并结合到推定的STAT结合DNA元件。此外，IL-6/sIL-6 R还激活了丝裂原活化蛋白（MAP）激酶，这些数据表明sIL-SR可以增强MG-63细胞对IL-6的反应性。因此，IL-6与sIL-6 R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节成骨细胞的分化和增殖。

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.