title: The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration.
abstract: BACKGROUND
  Myelinating Schwann cells (mSCs) form myelin in the peripheral nervous system. Because of the works by us and others, matrix metalloproteinase-9 (MMP-9) has recently emerged as an essential component of the Schwann cell signaling network during sciatic nerve regeneration.
  
  
  RESULTS
  In the present study, using the genome-wide transcriptional profiling of normal and injured sciatic nerves in mice followed by extensive bioinformatics analyses of the data, we determined that an endogenous, specific MMP-9 inhibitor [tissue inhibitor of metalloproteinases (TIMP)-1] was a top up-regulated gene in the injured nerve. MMP-9 capture followed by gelatin zymography and Western blotting of the isolated samples revealed the presence of the MMP-9/TIMP-1 heterodimers and the activated MMP-9 enzyme in the injured nerve within the first 24 h post-injury. MMP-9 and TIMP-1 co-localized in mSCs. Knockout of the MMP-9 gene in mice resulted in elevated numbers of de-differentiated/immature mSCs in the damaged nerve. Our comparative studies using MMP-9 knockout and wild-type mice documented an aberrantly enhanced proliferative activity and, accordingly, an increased number of post-mitotic Schwann cells, short internodes and additional nodal abnormalities in remyelinated nerves of MMP-9 knockout mice. These data imply that during the first days post-injury MMP-9 exhibits a functionally important anti-mitogenic activity in the wild-type mice. Pharmacological inhibition of MMP activity suppressed the expression of Na(v)1.7/1.8 channels in the crushed nerves.
  
  
  CONCLUSIONS
  Collectively, our data established an essential role of the MMP-9/TIMP-1 axis in guiding the mSC differentiation and the molecular assembly of myelin domains in the course of the nerve repair process. Our findings of the MMP-dependent regulation of Na(v) channels, which we document here for the first time, provide a basis for therapeutic intervention in sensorimotor pathologies and pain.
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Youngsoon
authors.initials: Y
authors.lastname: Kim
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Igor
authors.initials: I
authors.lastname: Shubayev
authors.forename: Calvin
authors.initials: C
authors.lastname: Lai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dolkas
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mizisin
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Shubayev
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000503:physiopathology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology* / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D015222:Sodium Channels / Q000378:metabolism; D013141:Spiro Compounds; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*
chemical_list: C529377:BAS 100; D015222:Sodium Channels; D013141:Spiro Compounds; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C572337:Mmp9 protein, rat