PMID- 24589419
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20211021
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 11
DP  - 2014 Mar 4
TI  - Inflammatory cascades mediate synapse elimination in spinal cord compression.
PG  - 40
LID - 10.1186/1742-2094-11-40 [doi]
AB  - BACKGROUND: Cervical compressive myelopathy (CCM) is caused by chronic spinal 
      cord compression due to spondylosis, a degenerative disc disease, and 
      ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported 
      to be an ideal animal model for CCM-related neuronal dysfunction, because they 
      develop spontaneous spinal cord compression without any artificial manipulation. 
      Previous histological studies showed that neurons are lost due to apoptosis in 
      CCM, but the mechanism underlying this neurodegeneration was not fully 
      elucidated. The purpose of this study was to investigate the pathophysiology of 
      CCM by evaluating the global gene expression of the compressed spinal cord and 
      comparing the transcriptome analysis with the physical and histological findings 
      in twy mice. METHODS: Twenty-week-old twy mice were divided into two groups 
      according to the magnetic resonance imaging (MRI) findings: a severe compression 
      (S) group and a mild compression (M) group. The transcriptome was analyzed by 
      microarray and RT-PCR. The cellular pathophysiology was examined by 
      immunohistological analysis and immuno-electron microscopy. Motor function was 
      assessed by Rotarod treadmill latency and stride-length tests. RESULTS: Severe 
      cervical calcification caused spinal canal stenosis and low functional capacity 
      in twy mice. The microarray analysis revealed 215 genes that showed significantly 
      different expression levels between the S and the M groups. Pathway analysis 
      revealed that genes expressed at higher levels in the S group were enriched for 
      terms related to the regulation of inflammation in the compressed spinal cord. M1 
      macrophage-dominant inflammation was present in the S group, and cysteine-rich 
      protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in 
      these spinal cords. Furthermore, C1q, which initiates the classical complement 
      cascade, was more upregulated in the S group than in the M group. The confocal 
      and electron microscopy observations indicated that classically activated 
      microglia/macrophages had migrated to the compressed spinal cord and eliminated 
      synaptic terminals. CONCLUSIONS: We revealed the detailed pathophysiology of the 
      inflammatory response in an animal model of chronic spinal cord compression. Our 
      findings suggest that complement-mediated synapse elimination is a central 
      mechanism underlying the neurodegeneration in CCM.
FAU - Takano, Morito
AU  - Takano M
FAU - Kawabata, Soya
AU  - Kawabata S
FAU - Komaki, Yuji
AU  - Komaki Y
FAU - Shibata, Shinsuke
AU  - Shibata S
FAU - Hikishima, Keigo
AU  - Hikishima K
FAU - Toyama, Yoshiaki
AU  - Toyama Y
FAU - Okano, Hideyuki
AU  - Okano H
AD  - Department of Orthopedic Surgery, Keio University School of Medicine, 35 
      Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. hidokano@a2.keio.jp.
FAU - Nakamura, Masaya
AU  - Nakamura M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140304
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (CCN1 protein, mouse)
RN  - 0 (Cysteine-Rich Protein 61)
RN  - 80295-33-6 (Complement C1q)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - EC 3.6.1.9 (nucleotide pyrophosphatase)
SB  - IM
MH  - Animals
MH  - Complement C1q/genetics/metabolism
MH  - Cysteine-Rich Protein 61/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation/genetics/*physiology
MH  - Inflammation/*genetics/*physiopathology
MH  - Macrophages/metabolism/pathology/ultrastructure
MH  - Magnetic Resonance Imaging
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Movement Disorders/genetics/physiopathology
MH  - Mutation/genetics
MH  - Pyrophosphatases/genetics/metabolism
MH  - Severity of Illness Index
MH  - Signal Transduction/immunology
MH  - Spinal Cord/metabolism/*pathology/ultrastructure
MH  - *Spinal Cord Compression/immunology/pathology/physiopathology
MH  - Synapses/metabolism/*pathology/ultrastructure
MH  - Time Factors
PMC - PMC3975877
EDAT- 2014/03/05 06:00
MHDA- 2014/09/17 06:00
PMCR- 2014/03/04
CRDT- 2014/03/05 06:00
PHST- 2014/01/05 00:00 [received]
PHST- 2014/02/17 00:00 [accepted]
PHST- 2014/03/05 06:00 [entrez]
PHST- 2014/03/05 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
PHST- 2014/03/04 00:00 [pmc-release]
AID - 1742-2094-11-40 [pii]
AID - 10.1186/1742-2094-11-40 [doi]
PST - epublish
SO  - J Neuroinflammation. 2014 Mar 4;11:40. doi: 10.1186/1742-2094-11-40.