title: Matrix metalloproteinase 2 and membrane type 1 matrix metalloproteinase co-regulate axonal outgrowth of mouse retinal ganglion cells.
abstract: Restoration of correct neural activity following central nervous system (CNS) damage requires the replacement of degenerated axons with newly outgrowing, functional axons. Unfortunately, spontaneous regeneration is largely lacking in the adult mammalian CNS. In order to establish successful regenerative therapies, an improved understanding of axonal outgrowth and the various molecules influencing it, is highly needed. Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases that were sporadically reported to influence axon outgrowth. Using an ex vivo retinal explant model, we were able to show that broad-spectrum MMP inhibition reduces axon outgrowth of mouse retinal ganglion cells (RGCs), implicating MMPs as beneficial factors in axonal regeneration. Additional studies, using more specific MMP inhibitors and MMP-deficient mice, disclosed that both MMP-2 and MT1-MMP, but not MMP-9, are involved in this process. Furthermore, administration of a novel antibody to MT1-MMP that selectively blocks pro-MMP-2 activation revealed a functional co-involvement of these proteinases in determining RGC axon outgrowth. Subsequent immunostainings showed expression of both MMP-2 and MT1-MMP in RGC axons and glial cells. Finally, results from combined inhibition of MMP-2 and β1-integrin were suggestive for a functional interaction between these molecules. Overall, our data indicate MMP-2 and MT1-MMP as promising axonal outgrowth-promoting molecules. Axonal regeneration in the central nervous system is lacking in adult mammals, thereby impeding recovery from injury to the nervous system. Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases that were sporadically reported to influence axon outgrowth. Inhibition of specific MMPs reduced neurite outgrowth from mouse retinal explants. Our data indicate MMP-2 and MT1-MMP as promising axonal outgrowth-promoting molecules and show a possible link between MMP-2 and β1-integrin in axon outgrowth.
authors.affiliation: Department of Biology, Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, KU Leuven, Leuven, Belgium.
authors.forename: Djoere
authors.initials: D
authors.lastname: Gaublomme
authors.forename: Tom
authors.initials: T
authors.lastname: Buyens
authors.forename: Lies
authors.initials: L
authors.lastname: De Groef
authors.forename: Michelle
authors.initials: M
authors.lastname: Stakenborg
authors.forename: Els
authors.initials: E
authors.lastname: Janssens
authors.forename: Signe
authors.initials: S
authors.lastname: Ingvarsen
authors.forename: Astrid
authors.initials: A
authors.lastname: Porse
authors.forename: Niels
authors.initials: N
authors.lastname: Behrendt
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D018093:Gelatinases / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000494:pharmacology / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019138:Antibodies, Blocking; D019012:Integrin beta1; D061965:Matrix Metalloproteinase Inhibitors; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: axon outgrowth; explant; integrin; matrix metalloproteinase (MMP); retina; retinal ganglion cell (RGC)