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.
References
[1]
Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56: 1552–1565.
[2]
McDonald D, Cheng C, Chen Y, Zochodne D (2006) Early events of peripheral nerve regeneration. Neuron Glia Biol 2: 139–147.
[3]
Cheng C, Zochodne DW (2002) In vivo proliferation, migration and phenotypic changes of Schwann cells in the presence of myelinated fibers. Neuroscience 115: 321–329.
[4]
Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annual review of neuroscience 30: 209–233.
[5]
Vargas ME, Barres BA (2007) Why is Wallerian degeneration in the CNS so slow? Annual review of neuroscience 30: 153–179.
[6]
Hall SM (1999) The biology of chronically denervated Schwann cells. Annals of the New York Academy of Sciences 883: 215–233.
Widera D, Heimann P, Zander C, Imielski Y, Heidbreder M, et al. (2011) Schwann cells can be reprogrammed to multipotency by culture. Stem cells and development 20: 2053–2064.
[9]
Wei Y, Gong K, Zheng Z, Liu L, Wang A, et al. (2010) Schwann-like cell differentiation of rat adipose-derived stem cells by indirect co-culture with Schwann cells in vitro. Cell proliferation 43: 606–616.
[10]
Lopatina T, Kalinina N, Karagyaur M, Stambolsky D, Rubina K, et al. (2011) Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PloS one 6: e17899.
[11]
Zujovic V, Thibaud J, Bachelin C, Vidal M, Coulpier F, et al. (2010) Boundary cap cells are highly competitive for CNS remyelination: fast migration and efficient differentiation in PNS and CNS myelin-forming cells. Stem cells 28: 470–479.
[12]
Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, et al. (2010) CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6: 578–590.
[13]
Hill CE, Moon LD, Wood PM, Bunge MB (2006) Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival. Glia 53: 338–343.
[14]
Jessen KR, Mirsky R (2005) The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 6: 671–682.
[15]
Taveggia C, Feltri ML, Wrabetz L (2010) Signals to promote myelin formation and repair. Nature reviews Neurology 6: 276–287.
[16]
Tapia M, Inestrosa NC, Alvarez J (1995) Early axonal regeneration: repression by Schwann cells and a protease? Exp Neurol 131: 124–132.
[17]
Chen YY, McDonald D, Cheng C, Magnowski B, Durand J, et al. (2005) Axon and Schwann cell partnership during nerve regrowth. J Neuropathol Exp Neurol 64: 613–622.
[18]
Clemence A, Mirsky R, Jessen KR (1989) Non-myelin-forming Schwann cells proliferate rapidly during Wallerian degeneration in the rat sciatic nerve. J Neurocytol 18: 185–192.
Triolo D, Dina G, Lorenzetti I, Malaguti M, Morana P, et al. (2006) Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage. J Cell Sci 119: 3981–3993.
[21]
Alvarez J, Moreno RD, Inestrosa NC (1995) Mitosis of Schwann cells and demyelination are induced by the amyloid precursor protein and other protease inhibitors in the rat sciatic nerve. Eur J Neurosci 7: 152–159.
[22]
Liu H, Kim Y, Chattopadhyay S, Shubayev I, Dolkas J, et al. (2010) MMP inhibition enhances the rate of nerve regeneration in vivo by promoting de-differentiation and mitosis of supporting Schwann cells. J Neuropathol Exp Neurol 69: 386–395.
[23]
Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562–573.
[24]
Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8: 221–233.
[25]
Ould-yahoui A, Tremblay E, Sbai O, Ferhat L, Bernard A, et al. (2009) A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons. PloS one 4: e8289.
[26]
Hansson J, Vasan RS, Arnlov J, Ingelsson E, Lind L, et al. (2011) Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: cohort study. PloS one 6: e16185.
[27]
Krekoski CA, Neubauer D, Graham JB, Muir D (2002) Metalloproteinase-dependent predegeneration in vitro enhances axonal regeneration within acellular peripheral nerve grafts. J Neurosci 22: 10408–10415.
[28]
Zuo J, Neubauer D, Dyess K, Ferguson TA, Muir D (1998) Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. Exp Neurol 154: 654–662.
[29]
Muir D (1994) Metalloproteinase-dependent neurite outgrowth within a synthetic extracellular matrix is induced by nerve growth factor. Exp Cell Res 210: 243–252.
[30]
Liu H, Shubayev V (2011) Matrix metalloproteinase-9 controls proliferation of NG2+ progenitor cells immediately after spinal cord injury. Exp Neurol.
[31]
Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6: 931–944.
[32]
Platt CI, Krekoski CA, Ward RV, Edwards DR, Gavrilovic J (2003) Extracellular matrix and matrix metalloproteinases in sciatic nerve. J Neurosci Res 74: 417–429.
[33]
Hartung HP, Kieseier BC (2000) The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system. J Neuroimmunol 107: 140–147.
[34]
Kobayashi H, Chattopadhyay S, Kato K, Dolkas J, Kikuchi S, et al. (2008) MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage. Mol Cell Neurosci 39: 619–627.
[35]
Chattopadhyay S, Myers RR, Janes J, Shubayev V (2007) Cytokine regulation of MMP-9 in peripheral glia: implications for pathological processes and pain in injured nerve. Brain Behav Immun 21: 561–568.
[36]
Shubayev VI, Angert M, Dolkas J, Campana WM, Palenscar K, et al. (2006) TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci 31: 407–415.
[37]
Kieseier BC, Hartung HP, Wiendl H (2006) Immune circuitry in the peripheral nervous system. Curr Opin Neurol 19: 437–445.
[38]
La Fleur M, Underwood JL, Rappolee DA, Werb Z (1996) Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1. J Exp Med 184: 2311–2326.
[39]
Chattopadhyay S, Shubayev VI (2009) MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia 57: 1316–1325.
[40]
Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6: 683–690.
[41]
Griffin JW, Hoffman PN (1984) Degeneration and regeneration in the peripheral nervous system. pp. 361–376, Chapter 322. Development and Regeneration of the Peripheral Nervous System.
[42]
Poliak S, Peles E (2003) The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci 4: 968–980.
[43]
Dib-Hajj SD, Black JA, Waxman SG (2009) Voltage-gated sodium channels: therapeutic targets for pain. Pain Med 10: 1260–1269.
[44]
Henry MA, Luo S, Foley BD, Rzasa RS, Johnson LR, et al. (2009) Sodium channel expression and localization at demyelinated sites in painful human dental pulp. J Pain 10: 750–758.
[45]
Nagarajan R, Le N, Mahoney H, Araki T, Milbrandt J (2002) Deciphering peripheral nerve myelination by using Schwann cell expression profiling. Proceedings of the National Academy of Sciences of the United States of America 99: 8998–9003.
[46]
D'Antonio M, Michalovich D, Paterson M, Droggiti A, Woodhoo A, et al. (2006) Gene profiling and bioinformatic analysis of Schwann cell embryonic development and myelination. Glia 53: 501–515.
[47]
Bosse F, Hasenpusch-Theil K, Kury P, Muller HW (2006) Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injury-dependent and reactivated developmental processes. Journal of neurochemistry 96: 1441–1457.
[48]
Kubo T, Yamashita T, Yamaguchi A, Hosokawa K, Tohyama M (2002) Analysis of genes induced in peripheral nerve after axotomy using cDNA microarrays. J Neurochem 82: 1129–1136.
[49]
Udalova IA, Ruhmann M, Thomson SJ, Midwood KS (2011) Expression and immune function of tenascin-C. Crit Rev Immunol 31: 115–145.
[50]
Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP (2007) Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 104: 20262–20267.
[51]
Ardi VC, Van den Steen PE, Opdenakker G, Schweighofer B, Deryugina EI, et al. (2009) Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway. J Biol Chem 284: 25854–25866.
[52]
Vega-Avelaira D, Geranton SM, Fitzgerald M (2009) Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Molecular pain 5: 70.
[53]
Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, et al. (2009) T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 29: 14415–14422.
[54]
Valder CR, Liu JJ, Song YH, Luo ZD (2003) Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. Journal of neurochemistry 87: 560–573.
[55]
Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, et al. (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America 99: 8360–8365.
[56]
Piccard H, Van den Steen PE, Opdenakker G (2007) Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins. J Leukoc Biol 81: 870–892.
[57]
Xu X, Jackson PL, Tanner S, Hardison MT, Abdul Roda M, et al. (2011) A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. PloS one 6: e15781.
[58]
Nunes GL, Simoes A, Dyszy FH, Shida CS, Juliano MA, et al. (2011) Mechanism of heparin acceleration of tissue inhibitor of metalloproteases-1 (TIMP-1) degradation by the human neutrophil elastase. PloS one 6: e21525.
[59]
Austin PJ, Moalem-Taylor G (2010) The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 229: 26–50.
Guy J, Ellis EA, Kelley K, Hope GM (1989) Spectra of G ratio, myelin sheath thickness, and axon and fiber diameter in the guinea pig optic nerve. J Comp Neurol 287: 446–454.
[62]
Chernousov MA, Yu WM, Chen ZL, Carey DJ, Strickland S (2008) Regulation of Schwann cell function by the extracellular matrix. Glia 56: 1498–1507.
[63]
Court FA, Wrabetz L, Feltri ML (2006) Basal lamina: Schwann cells wrap to the rhythm of space-time. Curr Opin Neurobiol 16: 501–507.
[64]
Gu Z, Cui J, Brown S, Fridman R, Mobashery S, et al. (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25: 6401–6408.
[65]
Court FA, Hewitt JE, Davies K, Patton BL, Uncini A, et al. (2009) A laminin-2, dystroglycan, utrophin axis is required for compartmentalization and elongation of myelin segments. J Neurosci 29: 3908–3919.
[66]
Occhi S, Zambroni D, Del Carro U, Amadio S, Sirkowski EE, et al. (2005) Both laminin and Schwann cell dystroglycan are necessary for proper clustering of sodium channels at nodes of Ranvier. J Neurosci 25: 9418–9427.
[67]
Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (2000) Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A 97: 5616–5620.
[68]
Milward E, Kim KJ, Szklarczyk A, Nguyen T, Melli G, et al. (2008) Cleavage of myelin associated glycoprotein by matrix metalloproteinases. J Neuroimmunol 193: 140–148.
[69]
Shubayev VI, Myers RR (2002) Endoneurial remodeling by TNFalpha- and TNFalpha-releasing proteases. A spatial and temporal co-localization study in painful neuropathy. J Peripher Nerv Syst 7: 28–36.
[70]
Kim CF, Moalem-Taylor G (2011) Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res 1405: 95–108.
[71]
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268: 10425–10432.
[72]
Yan L, Borregaard N, Kjeldsen L, Moses MA (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 276: 37258–37265.
[73]
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, et al. (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14: 331–336.
[74]
Zuo J, Ferguson TA, Hernandez YJ, Stetler-Stevenson WG, Muir D (1998) Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. J Neurosci 18: 5203–5211.
[75]
Oh LY, Larsen PH, Krekoski CA, Edwards DR, Donovan F, et al. (1999) Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. J Neurosci 19: 8464–8475.
[76]
Uhm JH, Dooley NP, Oh LY, Yong VW (1998) Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix. Glia 22: 53–63.
[77]
Larsen PH, Wells JE, Stallcup WB, Opdenakker G, Yong VW (2003) Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J Neurosci 23: 11127–11135.
[78]
Morello N, Bianchi FT, Marmiroli P, Tonoli E, Rodriguez Menendez V, et al. (2011) A role for hemopexin in oligodendrocyte differentiation and myelin formation. PloS one 6: e20173.
[79]
Moore CS, Milner R, Nishiyama A, Frausto RF, Serwanski DR, et al. (2011) Astrocytic Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Promotes Oligodendrocyte Differentiation and Enhances CNS Myelination. J Neurosci 31: 6247–6254.
[80]
Burg-Roderfeld M, Roderfeld M, Wagner S, Henkel C, Grotzinger J, et al. (2007) MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cells. Int J Oncol 30: 985–992.
[81]
Roeb E, Schleinkofer K, Kernebeck T, Potsch S, Jansen B, et al. (2002) The matrix metalloproteinase 9 (mmp-9) hemopexin domain is a novel gelatin binding domain and acts as an antagonist. J Biol Chem 277: 50326–50332.
[82]
Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, et al. (2008) The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci 28: 11571–11582.
[83]
Yu Q, Stamenkovic I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13: 35–48.
[84]
Dufour A, Zucker S, Sampson NS, Kuscu C, Cao J (2010) Role of matrix metalloproteinase-9 dimers in cell migration: design of inhibitory peptides. J Biol Chem 285: 35944–35956.
[85]
Lambert E, Bridoux L, Devy J, Dasse E, Sowa ML, et al. (2009) TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol 41: 1102–1115.
[86]
Lehmann HC, Kohne A, Bernal F, Jangouk P, Meyer Zu Horste G, et al. (2009) Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons. Glia 57: 479–489.
[87]
Werner SR, Dotzlaf JE, Smith RC (2008) MMP-28 as a regulator of myelination. BMC Neurosci 9: 83.
[88]
Court FA, Zambroni D, Pavoni E, Colombelli C, Baragli C, et al. (2011) MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains. J Neurosci 31: 12208–12217.
[89]
Zhao XL, Li GZ, Sun B, Zhang ZL, Yin YH, et al. (2010) MMP-mediated cleavage of beta-dystroglycan in myelin sheath is involved in autoimmune neuritis. Biochem Biophys Res Commun 392: 551–556.
[90]
Arroyo EJ, Scherer SS (2000) On the molecular architecture of myelinated fibers. Histochem Cell Biol 113: 1–18.
[91]
Siri A, Knauper V, Veirana N, Caocci F, Murphy G, et al. (1995) Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. J Biol Chem 270: 8650–8654.
[92]
Persson AK, Gasser A, Black JA, Waxman SG (2011) Nav1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. Exp Neurol 230: 273–279.
[93]
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(？Delta Delta C(T)) Method. Methods 25: 402–408.
[94]
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.
[95]
Mizisin AP, Bache M, DiStefano PS, Acheson A, Lindsay RM, et al. (1997) BDNF attenuates functional and structural disorders in nerves of galactose-fed rats. J Neuropathol Exp Neurol 56: 1290–1301.
