Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression

被引:110
作者
Chandra, Abhishek [1 ]
Lan, Shenghui [1 ,2 ]
Zhu, Ji [1 ]
Siclari, Valerie A. [1 ]
Qin, Ling [1 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA
[2] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed, Wuhan 430022, Hunan, Peoples R China
基金
美国国家卫生研究院;
关键词
MESENCHYMAL STEM-CELLS; FINGER TRANSCRIPTION FACTOR; GENE-EXPRESSION; OSTEOBLAST DIFFERENTIATION; REGULATORY FACTORS; BONE-FORMATION; IN-VITRO; T-CELLS; APOPTOSIS; PATHWAY;
D O I
10.1074/jbc.M112.447250
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:20488 / 20498
页数:11
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