Overcoming neurite‐inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix

摘要: Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of function related poor regeneration injured axons. Injured axons encounter several barriers regeneration, such as glial scar at injury site. The contains extracellular matrix (ECM) macromolecules deposited by reactive astrocytes response injury. ECM is rich chondroitin sulfate proteoglycans (CSPGs), that inhibit axonal growth. CSPGs consist a core protein with attachment sites for glycosaminoglycan (GAG) chains. An extensive literature demonstrates enzymatic removal GAG chains chondroitinase ABC permits some regrowth; however, remaining intact proteins also possess inhibitory domains. Because metalloproteinases degrade CSPGs, we have evaluated five (MMPs) protease-a disintegrin metalloproteinase thrombospondin motifs-4 (ADAMTS-4)-for their capacity overcome CSPG inhibition neuritic growth culture. were selected known expression after CNS injuries. Of MMPs, MMP-3, -7 -8 reduced or abolished neurite outgrowth on purified substrate an astrocyte-derived ECM. ADAMTS-4 attenuated neurites had additional benefits neither degrading laminin nor causing neurotoxicity. efficacy matched blocking EGFR signaling previously reported mediate inhibition. These findings highlight superior protease overcoming CNS.