Tissue inhibitor of metalloproteinase (TIMP)-1: The TIMPed balance of matrix metalloproteinases in the central nervous system

Astrocytes are intimately involved in the mechanisms of neural injury and repair. They participate in a variety of homeostatic functions and elicit repair responses as balance mechanisms. Currently, there is a growing appreciation of a more active role of astrocytes in neuronal signaling and function. One key homeostatic mechanism of astrocytes in tissue repair is maintained through their production of tissue inhibitors of metalloproteinases (TIMPs). The family of TIMPs (1-4) plays a central regulatory role as inhibitors of matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix maintenance and remodeling. Recently, TIMP-1, the inducible form, has been identified as a multifunctional molecule with divergent functions. It participates in wound healing and regeneration, cell morphology and survival, tumor metastasis, angiogenesis, and inflammatory responses. An imbalance of MMP/TIMP regulation has been implicated in several inflammatory diseases of the central nervous system (CNS). Here we review the conundrums of TIMP-1 regulation in CNS pathophysiology. We propose that astrocyte-TIMP-1 may play an important role in CNS homeostasis and disease. Astrocyte TIMP-1 expression is differentially regulated in inflammatory neurodegenerative diseases and may have significant therapeutic relevance. (C) 2003 Wiley-Liss, Inc.