Matrix Metalloproteinase-9/Gelatinase B Is Required for Process Outgrowth by Oligodendrocytes

Abstract

Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

“…In particular, oligodendrocyte-derived MMP-9 supports oligodendrogliosis and myelin restoration (Uhm et al 1998;Oh et al 1999;Larsen et al 2003). We previously demonstrated that MPTP treatment of both mice and monkeys induces a prominent oligodendrogliosis concomitant to the inflammatory process here described (Annese et al 2013).…”

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

“…Goat anti-mouse antibody conjugated to Cy-3 (Jackson ImmunoResearch) was used as the secondary antibody to detect labeled OLs. Mouse OLs extend several thread-like processes from soma, which facilitated the counting of the percentage of O1-positive cells with processes (Oh et al, 1999). The number of cells exhibiting processes at 24 hr was measured after treatment with the conditioned medium from bone marrow-derived macrophages (BMDM) from A1AR ϩ/ϩ or A1AR Ϫ/Ϫ .…”

Deficiency in Matrix Metalloproteinase Gelatinase B (MMP-9) Protects against Retinal Ganglion Cell Death after Optic Nerve Ligation

“…It employs fluorescein isothiocyanate-labeled DQ™-gelatin, (Molecular Probes, Eugene, OR), a substrate for gelatinolytic MMPs, which emits a fluorescent signal when cleaved (45). Unfixed sections of tissue prepared by cryostat were incubated overnight at 37°C with reaction buffer (0.05 M Tris-HCl, 0.15 M NaCl, 5 mM CaCl 2 , and 0.2 mM NaN 3 , pH 7.6) containing 40 g/ml DQ™-gelatin.…”