The TIMP family is comprised of four members, TIMP-1 through TIMP-4 [
1,
2,
4]. TIMPs were initially characterized as naturally-occurring inhibitors of the MMPs that were important for the maintenance of proteolytic balance and as such play important roles in a number of developmental and physiological remodelling processes, including cell migration, wound healing, neuronal survival and angiogenesis (reviewed in [
1,
2,
4]). The importance of the protective MMP-neutralizing effect of TIMP-1 in the CNS is best illustrated by the finding that TIMP-1 knockout mice display increased levels of MMP-9 activity, BBB breakdown and size of ischemic insult following focal cerebral ischemia [
15]. In support of this, a parallel study revealed that adenoviral delivery of TIMP-1 or TIMP-2 resulted in reduced levels of neuronal death in a model of global cerebral ischemia [
16]. TIMP-1 also plays an important MMP-dependent role in demyelinating disease, as illustrated by increased levels of demyelination and myelin pathology in TIMP-1 deficient mice in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) [
17]. In addition to the well-described MMP-dependent actions, in more recent years, several studies have demonstrated that TIMPs also have a number of MMP-independent actions, that include the regulation of cell growth and cell death (reviewed in [
4]). Specifically, it has been shown that TIMP-2 promotes neuronal differentiation by inhibiting cell proliferation, in an MMP-independent manner [
18,
19]. Exactly how these MMP-independent effects are mediated at the molecular level is still to be determined. However, studies on endothelial cells, highly relevant because of the influence of TIMPs on angiogenesis, suggest that TIMPs can bind to a variety of cell surface receptors, including the vascular endothelial growth factor (VEGF) receptor-2 [
20], and the α3β1 integrin [
21], raising the possibility that TIMPs signal through these specific receptors.
Recent studies have described two unexpected roles for TIMP-1 in the regulation of neural cell behaviour. First, TIMP-1 influences the growth and morphology of cortical neurons in an MMP-dependent manner; recombinant TIMP-1 reduced neurite length while dramatically increasing the size of growth cones [
22]. Second, a series of studies have demonstrated that TIMP-1 plays an important role in the generation and differentiation of oligodendrocytes [
23]. TIMP-1 knockout mice show reduced levels of myelin after induction of EAE [
17], whereas mice that express higher levels of TIMP-1 in their CNS exhibit attenuated demyelination in EAE [
24]. This is supported by the observations that TIMP-1 KO mice show delayed oligodendrocyte differentiation during development [
23], and that TIMP-1 KO neural stem cells (NSC) yield significantly fewer oligodendrocytes compared to wild type, an effect that can be reversed by the addition of recombinant TIMP-1 [
23].