The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration
Y Kim, AG Remacle, AV Chernov, H Liu, I Shubayev… - PloS one, 2012 - journals.plos.org
Y Kim, AG Remacle, AV Chernov, H Liu, I Shubayev, C Lai, J Dolkas, SA Shiryaev…
PloS one, 2012•journals.plos.orgBackground 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 …
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 …
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 Nav1.7/1.8 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 Nav channels, which we document here for the first time, provide a basis for therapeutic intervention in sensorimotor pathologies and pain.
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