PMID- 23720781
OWN - NLM
STAT- MEDLINE
DCOM- 20130927
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 28
DP  - 2013 Jul 12
TI  - Epidermal growth factor receptor (EGFR) signaling promotes proliferation and 
      survival in osteoprogenitors by increasing early growth response 2 (EGR2) 
      expression.
PG  - 20488-98
LID - 10.1074/jbc.M112.447250 [doi]
AB  - 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 TNFalpha-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.
FAU - Chandra, Abhishek
AU  - Chandra A
AD  - Department of Orthopaedic Surgery, Perelman School of Medicine, University of 
      Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
FAU - Lan, Shenghui
AU  - Lan S
FAU - Zhu, Ji
AU  - Zhu J
FAU - Siclari, Valerie A
AU  - Siclari VA
FAU - Qin, Ling
AU  - Qin L
LA  - eng
GR  - R25 CA101871/CA/NCI NIH HHS/United States
GR  - P30 AR050950/AR/NIAMS NIH HHS/United States
GR  - R25 CA101871-07/CA/NCI NIH HHS/United States
GR  - P30AR050950/AR/NIAMS NIH HHS/United States
GR  - R01 DK095803/DK/NIDDK NIH HHS/United States
GR  - K01 DK071988/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130529
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Early Growth Response Protein 2)
RN  - 0 (Egr2 protein, mouse)
RN  - 0 (Mcl1 protein, mouse)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Cell Survival
MH  - Early Growth Response Protein 2/genetics/*metabolism
MH  - ErbB Receptors/genetics/*metabolism
MH  - Gene Expression Profiling
MH  - Immunoblotting
MH  - MAP Kinase Signaling System
MH  - Mice
MH  - Myeloid Cell Leukemia Sequence 1 Protein
MH  - Oligonucleotide Array Sequence Analysis
MH  - Organ Culture Techniques
MH  - Osteoblasts/cytology/*metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - RNA Interference
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Signal Transduction
MH  - Skull/cytology/metabolism
PMC - PMC3711314
OTO - NOTNLM
OT  - Apoptosis
OT  - Bone
OT  - EGR2
OT  - Epidermal Growth Factor Receptor (EGFR)
OT  - Osteoporosis
OT  - Osteoprogenitors
OT  - Proliferation
EDAT- 2013/05/31 06:00
MHDA- 2013/09/28 06:00
PMCR- 2014/07/12
CRDT- 2013/05/31 06:00
PHST- 2013/05/31 06:00 [entrez]
PHST- 2013/05/31 06:00 [pubmed]
PHST- 2013/09/28 06:00 [medline]
PHST- 2014/07/12 00:00 [pmc-release]
AID - S0021-9258(20)45618-2 [pii]
AID - M112.447250 [pii]
AID - 10.1074/jbc.M112.447250 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Jul 12;288(28):20488-98. doi: 10.1074/jbc.M112.447250. Epub 
      2013 May 29.