Abstract
BackgroundMyelinating 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 FindingsIn 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/SignificanceCollectively, 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.
Highlights
Regenerative capacity of the peripheral nervous system depends on the remarkable phenotypic plasticity of Schwann cells (SCs) [1,2,3,4,5,6,7], increasingly employed in the regenerative medicine approaches [8,9,10,11,12,13]
The injury caused a multi-fold up-regulation of the genes that are directly linked to proteolysis, cell adhesion, cell signaling, and maintenance of the extracellular matrix, including tissue inhibitor of metalloproteinases (TIMP)-1, tenascin C (TNC) that is important in the immune response to tissue damage [42,48,49] and neutrophil gelatinase-associated lipocalin-2 (NGAL)/lipocalin-2 (LCN2), known to directly interact with matrix metalloproteinase-9 (MMP-9) [50,51]
In addition to the proliferative and proinflammatory growth-regulating factors identified by the earlier genome-wide profiling studies [45,46,47,48], our data reveal the novel important cellular components including matrix metalloproteinase (MMP)-9, TIMP-1, NGAL and CD44 in the injured nerve
Summary
Regenerative capacity of the peripheral nervous system depends on the remarkable phenotypic plasticity of Schwann cells (SCs) [1,2,3,4,5,6,7], increasingly employed in the regenerative medicine approaches [8,9,10,11,12,13]. It became evident that the SC interactions with axons during the early post-injury events influence the final outcome of nerve repair [2,16,17]. As both non-myelinating and myelinating SCs de-differentiate, they up-regulate the expression of glial fibrillary acidic protein (GFAP) [18,19], required for the subsequent proliferation of SCs and the initiation of axonal regeneration [20]. 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
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