title: Matrix metalloproteinase 3 deletion preserves denervated motor endplates after traumatic nerve injury.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Orthopaedic Surgery, University of California, Irvine, Irvine, CA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Chao
authors.forename: Derek
authors.initials: D
authors.lastname: Frump
authors.forename: Michael
authors.initials: M
authors.lastname: Lin
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Caiozzo
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: Oswald
authors.initials: O
authors.lastname: Steward
authors.forename: Ranjan
authors.initials: R
authors.lastname: Gupta
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D018171:Agrin / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D017353:Gene Deletion; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009045:Motor Endplate / Q000187:drug effects / Q000201:enzymology*; D009121:Muscle Denervation / Q000379:methods; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000503:physiopathology; D009416:Nerve Regeneration / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D014855:Wallerian Degeneration / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018171:Agrin; D018679:Cholinergic Agonists; D011950:Receptors, Cholinergic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D000109:Acetylcholine