Scientific Online Resource System

Scripta Scientifica Medica

Main characteristics and biological effects of martix metalloproteinases in the nervous system

Vanya Goranova Stefovska


Martix metalloproteinases (MMPs), one of the subgroups of the metzincins, are a large family of zinc-dependent endoproteases with multiple roles in extracellular matrix remodelling and modulation of signalling pathways. They are able to cleave all protein components of the extracellular matrix, as well as to activate or inactivate various signaling molecules, such as receptors, growth factors and adhesion molecules. MMPs are associated with many physiological functions such as embryonic development, angiogenesis and wound healing. Therefore, these proteinases are considered to be crucial mediators in many biological processes. Elevated MMP levels have also been implicated in an increasing number of injuries and disorders, such as inflammation, cancer and auto-immune diseases. Recent investigations highlight the beneficial and detrimental effects of MMPs in the nervous system in normal and pathological conditions. This review focuses on the role of MMPs as modulators of fundamental functions in the developing and adult nervous system and their potential to improve repair or regeneration after injury.


MMP domain structure; family members; substrates; neural plasticity

Full Text


Gross J, Lapiere C. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA. 1962;48 (6):1014-22.

Sekhon BS. Matrix metalloproteinases - an overview. Res Rep Biol. 2010;1:1-20.

Rawlings ND, Barrett AJ, Bateman A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2012;40:D343-50.

Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol. 2002;3(3):207-14.

Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003;200:448-64.

Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2006;11:1696-1701.

Van Hinsbergh VW, Koolwijk P. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res. 2008;78(2):203-12.

Tomlinson ML, Garcia-Morales C, Abu-Elmagd M, Wheeler GN. Three matrix metalloproteinases are required in vivo for macrophage migration during embryonic development. Mech Dev. 2008;125:1059-70.

Rodríguez D, Morrison CJ, Overall CM. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta. 2010;1803(1):39-54.

Mannello F. Multipotent mesenchymal stromal cell recruitment, migration, and differentiation: what have matrix metalloproteinases got to do with it? Stem Cells. 2006;24(8):1904-7.

Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 2000;14:2123-33.

Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221-33.

Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 2011;41:271-90.

Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463-516.

Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562-73.

Yong VW, Power C, Forsyth P, Edwards DR. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001;2(7):502-11.

Kumud P, Adlakha N, Mittal A. Multi class classification approcach for classification of ADAMs, MMPs and their subclasses. IACSIT. 2010;2(3):302-7.

Verma RP, Hansch C. Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem. 2007;15(6):2223-68.

Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827-39.

Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 2003;253(1-2):269-85.

Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007;26(8):587-96.

Bednarek N, Clement Y, Lelievre V, Olivier P, Loron G, Garnotel R et al. Ontogeny of MMPs and TIMPs in the murine neocortex. Ped Res. 2009;65:296-300.

Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg GA, Jaworski DM. Metzincin proteases and their inhibitors: foes or friends in nervous system physiology? J Neurosci. 2010;30:15337-57.

Ingraham CA, Park GC, Makarenkova HP, Crossin KL. Matrix metalloproteinase (MMP)-9 induced by Wnt signaling increases the proliferation and migration of embryonic neural stem cells at low O2 levels. J Biol Chem. 2011;286:17649-57.

Murase S, McKay RD. Matrix metalloproteinase-9 regulates survival of neurons in newborn hippocampus. J Biol Chem. 2012;287:12184-94.

Ayoub AE, Cai TQ, Kaplan RA, Luo J. Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex. J Comp Neurol. 2005;481(4):403-15.

Larsen PH, DaSilva AG, Conant K, Yong VW. Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. J Neurosci. 2006;26:2207-14.

Vaillant C, Meissirel C, Mutin M, Belin MF, Lund LR, Thomasset N. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol Cell Neurosci. 2003;24(2):395-408.

Ogier C, Bernard A, Cholle, AMT, Hanessian LED, Charton S, Khrestchatisky G et al. Matrix metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins. Glia. 2006;54:272-84.

Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci USA. 2006;103(17):6735-40.

Hehr CL, Hocking JC, McFarlane S. Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points. Development. 2005;132:3371-9.

Tian L, Stefanidakis M, Ning L, Van Lint P, Nyman-Huttunen H, Libert C et al. Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J Cell Biol. 2007;178:687-700.

Ethell IM, Ethell DW. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res. 2007;85:2813-23.

Girolamo F, Virgintino D, Errede M, Capobianco C, Bernardini N, Bertossi M et al. Involvement of metalloprotease-2 in the development of human brain microvessels. Histochem Cell Biol. 2004;122:261-70.

Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci. 2006;26(7):1923-34.

Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, Lim ST. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience. 2010;166:508-21.

Bozdagi O, Nagy V, Kwei KT, Huntley GW. In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J Neurophysiol. 2007;98:334-44.

Saygili E, Schauerte P, Pekassa M, Rackauskas G, Schwinger RH, Weis J et al. Sympathetic neurons express and secrete MMP-2 and MT1-MMP to control nerve sprouting via pro-NGF conversion. Cell Mol Neurobiol. 2011;31:17-25.

Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, Zornes PA et al. Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem. 2006;96(5):1227-41.

Wang XB, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci USA. 2008;105(49):19520-5.

Szklarczyk A, Lapinska J, Rylski M, McKay RD, Kaczmarek L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci. 2002;22(3):920-30.

Yong VW. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci. 2005;6(12):931-44.

Agrawal SM, Lau L, Yong VW. MMPs in the central nervous system: where the good guys go bad. Semin Cell Dev Biol. 2008;19(1):42-51.

Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ. Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist. 2010;16(2):156-70.

Barkho BZ, Munoz AE, Li X, Li L, Cunningham LA, Zhao X. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells. 2008;26(12):3139-49.

Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM et al. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci. 2006;26(13):3491-5.

Wang L, Zhang ZG, Zhang RL, Gregg SR, Hozeska-Solgot A, LeTourneau Y et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci. 2006;26:5996-6003.

Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005:50(4):329-39.

Vaillant C, Didier-Bazes M, Hutter A, Belin MF, Thomasset N. Spatiotemporal expression patterns of metalloproteinases and their inhibitors in the postnatal developing rat cerebellum. J Neurosci. 1999;19:4994-5004.

Ito A, Mukaiyama A, Itoh Y, Nagase H, Thogersen IB, Enghild JJ et al. Degradation of interleukin 1beta by matrix metalloproteinases. J Biol Chem. 1996;271(25):14657-60.

Duchossoy Y, Horvat JC, Stettler O. MMP-related gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. Mol Cell Neurosci. 2001;17:945-56.

Pizzi MA, Crowe MJ. Matrix metalloproteinases and proteoglycans in axonal regeneration. Exp Neurol. 2007;204(2):496-511.

Ahmed Z, Dent RG, Leadbeater WE, Smith C, Berry M, Logan A. Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Mol Cell Neurosci. 2005;28:64-78.

Shubayev VI, Myers RR. Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro. J Neurosci Res. 2004;77:229-39.

Murphy G, Gavrilovic J. Proteolysis and cell migration: creating a path? Curr Opin Cell Biol. 1999;11:614-21.

Pastrana E, Moreno-Flores MT, Gurzov EN, Avila J, Wandosell F, Diaz-Nido J. Genes associated with adult axon regeneration promoted by olfactory ensheathing cells: a new role for matrix metalloproteinase 2. J Neurosci. 2006;26:5347-59.

De Groef L, Van Hove I, Dekeyster E, Stalmans I, Moons L. MMPs in the neuroretina and optic nerve: modulators of glaucoma pathogenesis and repair? Invest Ophthalmol Vis Sci. 2014;55(3):1953-64.

Gaublomme D, Buyens T, De Groef L, Stakenborg M, Janssens E, Ingvarsen S et al. Matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase co-regulate axonal outgrowth of mouse retinal ganglion cells. J Neurochem. 2014;129(6):966-79.

Hsu JY, Bourguignon LY, Adams CM, Peyrollier K, Zhang H, Fandel T et al. Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci. 2008;28(50):13467-77.

Lehmann HC, Köhne A, Bernal F, Jangouk P, Meyer Zu Hörste G, Dehmel T et al. Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons. Glia. 2009;57:479-89.

Verslegers M, Lemmens K, Van Hove I, Moons L. Matrix metalloproteinase-2 and -9 as promising benefactors in development, plasticity and repair of the nervous system. Prog Neurobiol. 2013;105:60-78.

Larsen PH, Wells JE, Stallcup WB, Opdenakker G, Yong VW. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J Neurosci. 2003;23(35):11127-35.

Mantuano E, Inoue G, Li X, Takahashi K, Gaultie, A, Gonias SL et al. The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to lowdensity lipoprotein receptor-related protein. J Neurosci. 2008;28:11571-82.

About The Author

Vanya Goranova Stefovska
Dept. of Anatomy, Histology and Embryology, Medical University, Varna

Font Size