EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts
EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts
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EGFR-AKT-mTOR 激活介导培养成骨细胞中上皮调节蛋白诱导的多效性功能
DOI：
10.1007/s11010-014-2210-4
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发表时间：
2015-01-01
影响因子：
4.3
通讯作者：
Cui, Zhi-ming
中科院分区：
文献类型：
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作者：
Fan, Jian-bo;Liu, Wei;Cui, Zhi-ming
表皮生长因子（EGF）受体（EGFR）是调节成骨细胞功能的重要分子。在本研究中，我们探讨了表皮生长因子受体配体epiregulin在体外对成骨细胞功能的影响，并研究了其机制。我们发现，表皮调节蛋白诱导的EGFR激活的原代成骨细胞和成骨样MC 3 T3-E1细胞。同时，epiregulin可激活成骨细胞中的AKT-哺乳动物雷帕霉素靶蛋白（mTOR）和ERK-丝裂原活化蛋白激酶（MAPK）信号通路，这些信号通路可被EGFR抑制剂AG 1478或抗EGFR单克隆抗体（anti-EGFR）阻断。此外，在原代和MC 3 T3-E1成骨细胞中，epiregulin促进细胞增殖并增加碱性磷酸酶活性，同时抑制地塞米松（Dex）诱导的细胞死亡。表皮调节蛋白的这种作用在很大程度上被AG 1478或抗EGFR抑制。值得注意的是，AKT-mTOR抑制剂而不是Erk抑制剂减轻了成骨细胞中表皮调节蛋白诱导的上述多效性功能。同时，siRNA缺失mTOR复合物2（mTORC 2）的关键组分Sin 1也抑制了MC 3 T3-E1细胞中epiregulin发挥的作用。总之，这些结果表明，表皮调节蛋白诱导的多效性功能在培养的成骨细胞介导的EGFR-AKT-mTOR信号。
Epidermal growth factor (EGF) receptor (EGFR) emerges as an essential molecule for the regulating of osteoblast cellular functions. In the current study, we explored the effect of epiregulin, a new EGFR ligand, on osteoblast functions in vitro, and studied the underlying mechanisms. We found that epiregulin-induced EGFR activation in both primary osteoblasts and osteoblast-like MC3T3-E1 cells. Meanwhile, epiregulin activated AKT-mammalian target of rapamycin (mTOR) and Erk-mitogen-activated protein kinase (MAPK) signalings in cultured osteoblasts, which were blocked by EGFR inhibitor AG1478 or monoclonal antibody against EGFR (anti-EGFR). Further, in primary and MC3T3-E1 osteoblasts, epiregulin promoted cell proliferation and increased alkaline phosphatase activity, while inhibiting dexamethasone (Dex)-induced cell death. Such effects by epiregulin were largely inhibited by AG1478 or anti-EGFR. Notably, AKT-mTOR inhibitors, but not Erk inhibitors, alleviated epiregulin-induced above pleiotropic functions in osteoblasts. Meanwhile, siRNA depletion of Sin1, a key component of mTOR complex 2 (mTORC2), also suppressed epiregulin-exerted effects in MC3T3-E1 cells. Together, these results suggest that epiregulin-induced pleiotropic functions in cultured osteoblasts are mediated through EGFR-AKT-mTOR signalings.