The Expression of Matrix Metalloproteinase-12 by Oligodendrocytes Regulates Their Maturation and Morphological Differentiation

Abstract

Matrix metalloproteinases (MMPs) have important roles in many processes of the developing CNS requiring proteolytic activity such as the migration of neuronal precursors, axonal outgrowth, and vascularization. Another developmental event involving proteolysis is myelin formation, whereby the extensive processes elaborated from oligodendrocytes (OLs) enwrap axons. Here we find MMP-12 transcripts to be produced by OLs in much higher levels than other MMP members examined. MMP-12 activity correlated with the ability of OLs to extend processes in vitro, suggesting a role for MMP-12 in the morphological differentiation of OLs. This was corroborated by results that OL lineage cells from MMP-12 null mice were retarded in their ability to differentiate morphologically and that this deficiency was overcome by the exogenous addition of active MMP-12. Finally, the maturation of oligodendrocyte precursor cells (OPCs) to OLs was significantly reduced in cultures from MMP-12 null mice compared with wild-type controls. We conclude that OL lineage cells express MMP-12 during their maturation and that MMP-12 activity has functional involvement both in maturation of OPCs and in the ability of OPCs and OLs to extend processes.

Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

“…MMP-9 null mice on the 129/SvEv background were obtained from Dr. Zena Werb (University of California, San Francisco, San Francisco, CA) (Vu et al, 1998), whereas MMP-12 null mice on the same background were from Dr. Steve Shapiro (Harvard Medical School, Boston, MA) (Shipley et al, 1996). These mice were bred in-house and their genotype and lack of MMP-9 or -12 enzymatic activity have been confirmed previously (Oh et al, 1999;Larsen and Yong, 2004). To generate MMP-9 and -12 double-null mice, the single mutants were bred and offspring with mutations in both their MMP-9 and MMP-12 genes were identified by Southern blot.…”

“…The mouse MMP multiprobe set was kindly provided by Dr. Iain Campbell (The Scripps Research Institute, La Jolla, CA) (Pagenstecher et al, 1998). RPA was performed as described previously (Larsen and Yong, 2004). In brief, RNA samples were hybridized to the radioactive [␣-…”

“…OPCs were purified as described by Larsen and Yong (2004). Briefly, brains were removed from P3 wild-type and MMP-12 null mice and the cells were dissociated by 0.25% trypsin treatment (20 min).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In addition, investigation of serum, cerebrospinal fluid and brain tissue of patients with multiple sclerosis has revealed an increase in MMP-12 activity (Kurzepa et al, 2005). MMP-12 is also produced in large amounts by OLs in vitro to regulate their maturation and morphological differentiation (Larsen and Yong, 2004). Many growth factors are involved in the normal development of myelin, among these the insulin-like growth factor 1 (IGF-1) is very important for oligodendrocyte maturation (D'Ercole et al, 2002).…”

Histone deacetylase inhibition-mediated cytotoxicity of oligodendrocytes.

“…Furthermore, with passage, subtle cellular changes occur resulting in a molecularly different cell type than what was originally isolated (Lin et aI., 2006). Lastly, nearly all existing primary OPC cultures from rodent models rely on more premature markers A2B5 and NG2 which may not have as extensive oligodendrogliallineage commitment (Larsen and Yong, 2004;Hamanoue et aI., 2009). Primary OPC cultures will be better served using a later stage marker than is more limited to the oligodendroglia I lineage but still maintain their proliferative capacity.…”