NEURONAL MATRIX METALLOPROTEINASE-2 DEGRADES AND INACTIVATES A NEURITE-INHIBITING CHONDROITIN SULFATE PROTEOGLYCAN

Chondroitin sulfate proteoglycans (CSPGs) are implicated in the regula tion of axonal growth. We previously reported that the neurite-promoti ng activity of laminin is inhibited by association with a Schwann cell -derived CSPG and that endoneurial laminin may be inhibited by this CS PG as well [Zuo J, Hernandez YJ, Muir D (1998) Chondroitin sulfate pro teoglycan with neurite-inhibiting activity is upregulated after periph eral nerve injury. J Neurobiol 34:41-54]. Mechanisms regulating axonal growth were studied by using an in vitro bioassay in which regenerati ng embryonic dorsal root ganglionic neurons (DRGn) were grown on secti ons of normal adult nerve. DRGn achieved slow neuritic growth on secti ons of normal nerve, which was reduced significantly by treatment with metalloproteinase inhibitors. Similar results were obtained on a synt hetic substratum composed of laminin and inhibitory CSPG. DRGn express ed the matrix metalloproteinase, MMP-2, which was transported to the g rowth cone. Recombinant MMP-2 inactivated the neurite-inhibiting CSPG without hindering the neurite-promoting potential of laminin. Similarl y, neuritic growth by DRGn cultured on normal nerve sections was incre ased markedly by first treating the nerve sections with MMP-2. The pro teolytic deinhibition by MMP-2 was equivalent to and nonadditive with that achieved by chondroitinase, suggesting that both enzymes inactiva ted inhibitory CSPG. Additionally, the increases in neuritic growth re sulting from treating nerve sections with MMP-2 or chondroitinase were blocked by anti-laminin antibodies. From these results we conclude th at MMP-2 provides a mechanism for the deinhibition of laminin in the e ndoneurial basal lamina and may play an important role in the regenera tion of peripheral nerve.