PMID- 26079709
OWN - NLM
STAT- MEDLINE
DCOM- 20160819
LR  - 20181202
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 82
DP  - 2015 Oct
TI  - MMP-3 secreted from endothelial cells of blood vessels after spinal cord injury 
      activates microglia, leading to oligodendrocyte cell death.
PG  - 141-151
LID - S0969-9961(15)00220-X [pii]
LID - 10.1016/j.nbd.2015.06.002 [doi]
AB  - The activation of microglia after spinal cord injury (SCI) contributes to 
      secondary damage by producing pro-inflammatory cytokines and mediators, leading 
      to cell death of oligodendrocytes and neurons. Here, we show that matrix 
      metalloprotease-3 (MMP-3) produced and secreted in the endothelial cells of blood 
      vessels after SCI mediates microglial activation. MMP-3 was produced and secreted 
      in bEnd.3 cells, a mouse brain-derived endothelial cell line, by oxygen-glucose 
      deprivation/reoxygenation (OGD/RO). OGD/RO-induced MMP-3 expression and activity 
      was also significantly inhibited by ghrelin, which was dependent on the ghrelin 
      receptor GHS-R1a. Furthermore, the secreted MMP-3 from OGD/RO-induced bEnd.3 
      cells activated BV-2 cells, a murine microglial cell line. We also found that 
      microglial activation after SCI was attenuated in MMP-3 knockout (KO) mice 
      compared with wild type (WT) mice. Both p38 mitogen-activated protein kinase 
      (MAPK) activation and pro-nerve growth factor (proNGF) production were more 
      inhibited in MMP-3 KO than WT mice at 5d after injury. When WT mice were treated 
      with Mmp-3 siRNA after injury, MMP-3 activity, microglial activation, p38MAPK 
      activation and proNGF expression were significantly inhibited. Ghrelin treatment 
      also significantly inhibited MMP-3 expression and activation after SCI, which was 
      dependent on GHS-R1a. Finally, RhoA activation and oligodendrocyte cell death 
      after injury were attenuated by Mmp-3 siRNA or ghrelin treatment compared with 
      vehicle control. Thus, our study indicates that MMP-3 produced in blood vessel 
      endothelial cells after SCI serves as an endogenous molecule for microglial 
      activation followed by p38MAPK activation and proNGF production, and further 
      indicates that the protective effect of ghrelin on oligodendrocytes cell death 
      may be at least partly mediated by the inhibition of MMP-3-induced microglial 
      activation after SCI.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Lee, Jee Y
AU  - Lee JY
AD  - Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee 
      University, Seoul 130-701, Republic of Korea. Electronic address: 
      jeeyoun@hu.ac.kr.
FAU - Choi, Hae Y
AU  - Choi HY
AD  - Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee 
      University, Seoul 130-701, Republic of Korea. Electronic address: 
      neuron@khu.ac.kr.
FAU - Yune, Tae Y
AU  - Yune TY
AD  - Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee 
      University, Seoul 130-701, Republic of Korea; Department of Biochemistry and 
      Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, 
      Republic of Korea. Electronic address: tyune@khu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150612
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Ghrelin)
RN  - 0 (Nerve Growth Factors)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Cell Death/drug effects/*physiology
MH  - Cell Line
MH  - Endothelial Cells/drug effects/*metabolism/pathology
MH  - Endothelium, Vascular/drug effects/*metabolism/pathology
MH  - Ghrelin/pharmacology
MH  - Matrix Metalloproteinase 3/*metabolism
MH  - Mice
MH  - Microglia/drug effects/*metabolism/pathology
MH  - Nerve Growth Factors/metabolism
MH  - Neurons/drug effects/metabolism/pathology
MH  - Oligodendroglia/drug effects/*metabolism/pathology
MH  - Spinal Cord Injuries/*metabolism/pathology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
OTO - NOTNLM
OT  - Matrix metalloprotease-3
OT  - Microglia
OT  - Oligodendrocyte
OT  - RhoA
OT  - Spinal cord injury
EDAT- 2015/06/17 06:00
MHDA- 2016/08/20 06:00
CRDT- 2015/06/17 06:00
PHST- 2014/11/24 00:00 [received]
PHST- 2015/06/02 00:00 [revised]
PHST- 2015/06/08 00:00 [accepted]
PHST- 2015/06/17 06:00 [entrez]
PHST- 2015/06/17 06:00 [pubmed]
PHST- 2016/08/20 06:00 [medline]
AID - S0969-9961(15)00220-X [pii]
AID - 10.1016/j.nbd.2015.06.002 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2015 Oct;82:141-151. doi: 10.1016/j.nbd.2015.06.002. Epub 2015 Jun 
      12.