Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression
Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression
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DOI：
10.1074/jbc.m112.447250
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发表时间：
2013-07-12
影响因子：
4.8
通讯作者：
Qin, Ling
中科院分区：
文献类型：
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作者：
Chandra, Abhishek;Lan, Shenghui;Qin, Ling
维持骨结构需要从骨祖细胞池中不断地产生成骨细胞。我们之前对成骨细胞系细胞中具有表皮生长因子受体(EGFR)特异性失活的小鼠的研究表明，EGFR通过扩大间充质祖细胞的数量来刺激骨形成。EGFR配体是骨祖细胞池的有效调节者，但其潜在的机制在很大程度上尚不清楚。在这里，我们证明了EGFR的激活主要通过MAPK/ERK通路促进细胞增殖，抑制血清耗竭诱导的或肿瘤坏死因子α诱导的细胞凋亡，从而增加成骨细胞的数量。小鼠颅骨器官培养显示，EGF可增加增殖细胞数，减少凋亡细胞数，从而导致成骨细胞数量增加。对成骨前体细胞系MC3T3细胞的微阵列分析显示，EGFR信号刺激抗凋亡蛋白MCL1和一系列EGR转录因子(Egr1、-2和-3)的表达。EGF上调MCL1和EGR2的作用在接近颅骨表面的骨祖细胞中得到进一步证实。EGRs的共同抑制因子NAB2的过表达减弱了EGF诱导的成骨细胞数量的增加。有趣的是，下调EGR2的表达，而不是Egr1或-3的表达，会产生类似的效果。通过使用抑制物、腺病毒过表达和siRNA方法，我们证明了EGFR信号通路激活MAPK/ERK通路以刺激EGR2的表达，进而导致细胞生长和MCL1介导的细胞存活。综上所述，我们的数据清楚地表明，EGFR诱导的EGR2表达对成骨前体细胞的维持和新骨形成至关重要。
Maintaining bone architecture requires continuous generation of osteoblasts from osteoprogenitor pools. Our previous study of mice with epidermal growth factor receptor (EGFR) specifically inactivated in osteoblast lineage cells revealed that EGFR stimulates bone formation by expanding the population of mesenchymal progenitors. EGFR ligands are potent regulators for the osteoprogenitor pool, but the underlying mechanisms are largely unknown. Here we demonstrate that activation of EGFR increases the number of osteoprogenitors by promoting cell proliferation and suppressing either serum depletion-induced or TNF alpha-induced apoptosis mainly through the MAPK/ERK pathway. Mouse calvarial organ culture revealed that EGF elevated the number of proliferative cells and decreased the number of apoptotic cells, which led to increased osteoblasts. Microarray analysis of MC3T3 cells, an osteoprogenitor cell line, revealed that EGFR signaling stimulates the expression of MCL1, an antiapoptotic protein, and a family of EGR transcription factors (EGR1, -2, and -3). The up-regulation of MCL1 and EGR2 by EGF was further confirmed in osteoprogenitors close to the calvarial bone surface. Overexpression of NAB2, a co-repressor for EGRs, attenuated the EGF-induced increase in osteoprogenitor number. Interestingly, knocking down the expression of EGR2, but not EGR1 or -3, resulted in a similar effect. Using inhibitor, adenovirus overexpression, and siRNA approaches, we demonstrate that EGFR signaling activates the MAPK/ERK pathway to stimulate the expression of EGR2, which in turn leads to cell growth and MCL1-mediated cell survival. Taken together, our data clearly demonstrate that EGFR-induced EGR2 expression is critical for osteoprogenitor maintenance and new bone formation.