PMID- 23281061
OWN - NLM
STAT- MEDLINE
DCOM- 20130521
LR  - 20131121
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Linking)
VI  - 73
IP  - 2
DP  - 2013 Feb
TI  - Matrix metalloproteinase 3 deletion preserves denervated motor endplates after 
      traumatic nerve injury.
PG  - 210-23
LID - 10.1002/ana.23781 [doi]
AB  - OBJECTIVE: Traumatic peripheral nerve injuries often produce permanent functional 
      deficits despite optimal surgical and medical management. One reason for the 
      impaired target organ reinnervation is degradation of motor endplates during 
      prolonged denervation. Here we investigate the effect of preserving agrin on the 
      stability of denervated endplates. Because matrix metalloproteinase 3 (MMP3) is 
      known to degrade agrin, we examined the changes in endplate structure following 
      traumatic nerve injury in MMP3 knockout mice. METHODS: After creation of a 
      critical size nerve defect to preclude reinnervation, we characterized receptor 
      area, receptor density, and endplate morphology in denervated plantaris muscles 
      in wild-type and MMP3 null mice. The level of agrin and muscle-specific kinase 
      (MuSK) was assessed at denervated endplates. In addition, denervated muscles were 
      subjected to ex vivo stimulation with acetylcholine. Finally, reinnervation 
      potential was compared after long-term denervation. RESULTS: In wild-type mice, 
      the endplates demonstrated time-dependent decreases in area and receptor density 
      and conversion to an immature receptor phenotype. In striking contrast, all 
      denervation-induced changes were attenuated in MMP3 null mice, with endplates 
      retaining their differentiated form. Agrin and MuSK were preserved in endplates 
      from denervated MMP3 null animals. Furthermore, denervated muscles from MMP3 null 
      mice demonstrated greater endplate efficacy and reinnervation. INTERPRETATION: 
      These results demonstrate a critical role for MMP3 in motor endplate remodeling, 
      and reveal a potential target for therapeutic intervention to prevent motor 
      endplate degradation following nerve injury.
CI  - Copyright (c) 2012 American Neurological Association.
FAU - Chao, Tom
AU  - Chao T
AD  - Department of Orthopaedic Surgery, University of California, Irvine, Irvine, CA, 
      USA.
FAU - Frump, Derek
AU  - Frump D
FAU - Lin, Michael
AU  - Lin M
FAU - Caiozzo, Vincent J
AU  - Caiozzo VJ
FAU - Mozaffar, Tahseen
AU  - Mozaffar T
FAU - Steward, Oswald
AU  - Steward O
FAU - Gupta, Ranjan
AU  - Gupta R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121231
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (Agrin)
RN  - 0 (Cholinergic Agonists)
RN  - 0 (Receptors, Cholinergic)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.17 (Mmp3 protein, mouse)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/pharmacology
MH  - Agrin/metabolism
MH  - Animals
MH  - Cell Line
MH  - Cholinergic Agonists/pharmacology
MH  - Disease Models, Animal
MH  - Gene Deletion
MH  - Male
MH  - Matrix Metalloproteinase 3/*genetics/*metabolism
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Knockout
MH  - Motor Activity/physiology
MH  - Motor Endplate/drug effects/*enzymology
MH  - Muscle Denervation/methods
MH  - Muscle, Skeletal/drug effects/innervation/pathology
MH  - Muscular Atrophy/metabolism/physiopathology
MH  - Nerve Regeneration/*physiology
MH  - Peripheral Nerve Injuries/*metabolism/*physiopathology
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Receptors, Cholinergic/metabolism
MH  - Wallerian Degeneration/metabolism/physiopathology
EDAT- 2013/01/03 06:00
MHDA- 2013/05/23 06:00
CRDT- 2013/01/03 06:00
PHST- 2012/06/12 00:00 [received]
PHST- 2012/08/29 00:00 [revised]
PHST- 2012/09/24 00:00 [accepted]
PHST- 2013/01/03 06:00 [entrez]
PHST- 2013/01/03 06:00 [pubmed]
PHST- 2013/05/23 06:00 [medline]
AID - 10.1002/ana.23781 [doi]
PST - ppublish
SO  - Ann Neurol. 2013 Feb;73(2):210-23. doi: 10.1002/ana.23781. Epub 2012 Dec 31.