An alternate perspective on the roles of TIMPs and MMPs in pathology.

Tissue inhibitors of metalloproteinases (TIMPs) are pleiotropic extracellular proteins. TIMPs are recognized as endogenous regulators of matrix metalloproteinases (MMPs), a large family of extracellular enzymes with proteolytic activities that participate in cellular homeostasis, adaptation, and tissue remodeling. In addition to their roles as endogenous potent MMP inhibitors, accumulating evidence indicates important physiological roles for TIMPs that are independent of their ability to block MMP activities. For instance, MMP-independent actions of TIMP-1 in the central nervous system have been implicated in synaptic plasticity, neuroprotection, oncogenesis, and oligodendrocyte differentiation. Expression of TIMP-1 is dramatically increased in response to a variety of injurious and inflammatory insults. In the context of disease pathogenesis, MMP and TIMP expression are interpreted with respect to the proteolytic consequences of increased MMP/TIMP ratios. Here, we provide an alternative perspective on the homeostatic balance of TIMP and MMP proteins, whereby consideration is given to the possible role of MMPs as cognate inhibitors of the signaling functions of TIMPs. Thus, MMPs may regulate the receptor-mediated actions of TIMPs, inasmuch as TIMPs are themselves inhibitors of MMP-mediated proteolytic activities. This broader view reflects our emerging understanding that TIMP signaling and MMP inhibition represent two important functions of TIMPs that have the potential to affect tissue pathology.