%0 Journal Article
%T Matrix Metalloproteinases in Neuropathic Pain and Migraine: Friends, Enemies, and Therapeutic Targets
%A Shaheen E. Lakhan
%A Mihaela Avramut
%J Pain Research and Treatment
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/952906
%X Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent endopeptidases that mediate extracellular matrix turnover and associated processes, such as cell survival, growth, and differentiation. This paper discusses important functions of MMP in the normal and injured nervous system, focusing on the role played by these proteases in neurological pain syndromes, most prominently in neuropathic pain and migraine headaches. In the past decade, metalloproteinases emerged as key modulators of neuropathic pain, with MMP-9 acting as an initiator of the neuropathic cascade. Increased MMP activity was detected in migraine patients, independent of aura, in tight association with metabolic derangements. The therapeutic implications of MMP inhibition are considered in the context of neurogenic pain regulation. 1. Background Matrix metalloproteinases (MMPs) are a family of over twenty zinc-dependent endopeptidases that play essential roles in a wide range of proteolytic processes. Their first-recognized and most prominent function is in cleaving components of the extracellular matrix (ECM). Additional substrates identified in recent years include other proteinases, chemotactic factors, growth factors, cell surface receptors, and cell adhesion molecules [1¨C3]. Acting upon all these substrates allows metalloproteinases to influence a multitude of processes, from cellular differentiation and migration to signaling, survival, and apoptosis (Table 1). Although most MMPs are secreted molecules, several transmembrane and glycosylphosphatidylinositol-anchored membrane proteins are also included in this family. According to their structure and substrate specificity, MMPs are categorized as collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and -11), membrane-type MMPs (MMP-14 or MT1-MMP, MMP-15 or MT2-MMP, MMP-16 or MT3-MMP, MMP-17 or MT4-MMP, MMP-24 or MT5-MMP, and MMP-25 or MT6-MMP), and other MMPs [3]. Table 1: Matrix metalloproteinases modulate tissue structure and cellular activities by participating in complex biological processes. In accordance with MMP involvement in tissue turnover, their activity undergoes tight regulation through multiple mechanisms, including transcription and translation of proprotease genes, and proform activation. Although most members of the protease family are not expressed constitutively, they are rapidly upregulated when cytokines, chemokines, growth factors, ECM components, and other transcriptional regulators act upon the cell [3, 4]. Most MMPs are translated as
%U http://www.hindawi.com/journals/prt/2012/952906/