The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration

PLoS One. 2012;7(3):e33664. doi: 10.1371/journal.pone.0033664. Epub 2012 Mar 16.


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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Female
  • Ganglia, Spinal / physiopathology
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Sheath / physiology*
  • Nerve Regeneration / genetics
  • Nerve Regeneration / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Schwann Cells / cytology*
  • Schwann Cells / physiology*
  • Sciatic Nerve / injuries
  • Sciatic Nerve / pathology
  • Sciatic Nerve / physiopathology
  • Sodium Channels / metabolism
  • Spiro Compounds
  • Tissue Inhibitor of Metalloproteinase-1 / physiology*


  • BAS 100
  • Sodium Channels
  • Spiro Compounds
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • Mmp9 protein, rat