OLIGODENDROCYTES UTILIZE A MATRIX METALLOPROTEINASE, MMP-9, TO EXTENDPROCESSES ALONG AN ASTROCYTE EXTRACELLULAR-MATRIX

Matrix metalloproteinases (MMPs), the key effecters of extracellular m atrix remodeling, have been demonstrated to regulate the extension of neurites from neuronal cell bodies. In this report we have addressed t he hypothesis that oligodendrocytes (OLs) may utilize a similar mechan ism in extending their processes during the initial phase of myelinati on. Furthermore, given our previous findings linking protein kinase C (PKC) to the OL process outgrowth, we tested the postulate that this s ignal transduction pathway may regulate MMPs and thus the process outg rowth phenotype. We demonstrate that in response to pharmacologic acti vators of PKC, cultured human OLs augment their process extension with a concomitant increase in the activity of an MMP, MMP-9, as measured by gelatin zymography. Similarly, the phorbol ester-enhanced process e xtension and increased MMP-9 activity were both inhibited by calphosti n C, a selective PKC inhibitor. Also, MMP inhibitors such as 1,10-phen anthroline and synthetic dipeptides that inactivate the MMP catalytic site negated the 4 beta-phorbol-12,13-dibutyrate (PDB)-mediated proces s extension, further supporting the key role of MMPs in process extens ion in vitro. Finally, the elevation of MMP-9 protein expression in th e mouse corpus callosum, a tissue rich in OL and myelin, coincided wit h the previously documented temporal increase in myelination that occu rs postnatally. Taken together, these data suggest that MMP-9 constitu tes an important mediator of OL process outgrowth, and that this prote ase in turn can be regulated by PKC. The results are relevant not only to the initial steps of myelination during development, but also to t he attempted remyelination that has been shown to occur in pathologic conditions such as MS. (C) 1998 Wiley-Liss, Inc.