The MMP-9/TIMP-1 Axis Controls the Status of Differentiation and Function of Myelin-Forming Schwann Cells in Nerve Regeneration

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.

TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice

“…The lack of protease interaction of these mutants might result in an increased amount of proteins available for receptor binding and signal transmission, a perspective that has been recently proposed. 43 Effects of TIMP-1 on proliferation and differentiation have been described for several cell types, including tumor cells, 44 neuronal cells, 45 and mesenchymal stem cells. 17 Interestingly, TIMP-1 was concurrently discovered as erythroid potentiating activity (EPA), 46 a factor that stimulated proliferation of human erythroid progenitors, 47 and this effect was found to be independent of protease inhibition.…”

“…Effects of TIMP-1 on proliferation and differentiation have been described for several cell types, including tumor cells, 44 neuronal cells, 45 and mesenchymal stem cells.…”

Genetics of chronic post-surgical pain: a crucial step toward personal pain medicine

“…In addition, we and others have studied the changes in gene expression levels in the dorsal root ganglia and in the spinal cord after nerve injury. [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] When the human genome is mapped for genes controlling CPSP, these comparative studies will facilitate identifying conserved loci for CPSP in mice and humans. This knowledge will become important when developing novel analgesics in mice, which share CPSP genetic ''architecture'' similar to that in humans.…”

Matrix Metalloproteinase-14 Both Sheds Cell Surface Neuronal Glial Antigen 2 (NG2) Proteoglycan on Macrophages and Governs the Response to Peripheral Nerve Injury

“…laminin) from degradation, suppressing the algesic action of MMP-2 (21), and stimulating the regenerative program in the sensory neurons, the selective, local, and short term inhibition of MMP-14 activity promoted axonal growth and reversed the established hypersensitivity arising from PNS damage. Caution, however, is required in developing the sustained or late stage MMP-14 inhibitor therapy as this therapy may also target certain functions that are beneficial to nerve repair, such as the MMP-2-mediated degradation of inhibitory CSPGs (25,26) and myelination (20,64,65).…”

“…Conversely, targeting of the upstream regulator of pro-MMP-2 activation, MMP-14, represents a valuable alternative. Studies of MMP-14 in the PNS have thus far been limited to the evidence of its gene expression (20,27).…”