MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

Abstract

Matrix metalloproteinase-9 (MMP-9) is a member of the metzincin family of mostly extracellularly operating proteases. Despite the fact that all of these enzymes might be target promiscuous, with largely overlapping catalogs of potential substrates, MMP-9 has recently emerged as a major and apparently unique player in brain physiology and pathology. The specificity of MMP-9 may arise from its very local and time-restricted actions, even when released in the brain from cells of various types, including neurons, glia, and leukocytes. In fact, the quantity of MMP-9 is very low in the naive brain, but it is markedly activated at the levels of enzymatic activity, protein abundance, and gene expression following various physiological stimuli and pathological insults. Neuronal MMP-9 participates in synaptic plasticity by controlling the shape of dendritic spines and function of excitatory synapses, thus playing a pivotal role in learning, memory, and cortical plasticity. When improperly unleashed, MMP-9 contributes to a large variety of brain disorders, including epilepsy, schizophrenia, autism spectrum disorder, brain injury, stroke, neurodegeneration, pain, brain tumors, etc. The foremost mechanism of action of MMP-9 in brain disorders appears to be its involvement in immune/inflammation responses that are related to the enzyme's ability to process and activate various cytokines and chemokines, as well as its contribution to bloodbrain barrier disruption, facilitating the extravasation of leukocytes into brain parenchyma. However, another emerging possibility (i.e., the control of MMP-9 over synaptic plasticity) should not be neglected. The translational potential of MMP-9 has already been recognized in both the diagnosis and treatment domains. The most striking translational aspect may be the discovery of MMP-9 up-regulation in a mouse model of Fragile X syndrome, quickly followed by human studies and promising clinical trials that have sought to inhibit MMP-9. With regard to diagnosis, suggestions have been made to use MMP-9 alone or combined with tissue inhibitor of matrix metalloproteinase-1 or brain-derived neurotrophic factor as disease biomarkers.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…The b3 subunit is physically coupled to AMPARs via their cytoplasmic domains (Pozo et al, 2012) and is required for activitydependent synaptic scaling of glutamatergic synapses . For more information on the ECM, MMPs, and tissue inhibitors of MMPs, see Seals and Courtneidge (2003), Brew and Nagase (2010) Scofield et al (2015), Smith et al (2015a,b), and Vafadari et al, (2015).…”

A Glitch in the Matrix: Aberrant Extracellular Matrix Proteolysis Contributes to Alcohol Seeking

“…The interesting clinical data in this report demonstrating that a known gain-of-function single nucleotide polymorphism in the MMP9 gene is associated with increased motivation to consume alcohol despite negative consequences adds to literature encouraging examination of MMP-9 as a pharmacotherapeutic target for addiction. Previously, increased serum MMP-9 expression has been demonstrated in both alcohol-dependent and heroin-dependent patients (5). Outside of drug addiction, either serum MMP-9 levels or the C-1562T polymorphism have been correlated with a number of disorders, most notably mild cognitive impairment, Alzheimer’s disease, major depressive disorder, and fragile X syndrome.…”

“…Thus, by virtue of its remodeling activity in the extracellular matrix, MMP-9 is uniquely situated to affect many diverse signaling pathways relevant to drug addiction. While MMP-9 is well established as both necessary and sufficient for long-term potentiation at hippocampal synapses, very little is known about its role in other brain sites, including the CeA (5). Previously, Michaluk et al (6) showed that rats that over-express an autoactive form of MMP-9 have greater numbers of long, thin spines, with no change in mushroom- or stubby-type spines in the hippocampus.…”

“…(5)], although as of yet no successful MMP-9–directed drug candidates have come to fruition (5). Minocycline is a commonly used tetracycline antibiotic that has been shown to reduce MMP-9 activity and expression, raising the question of whether this drug could be effectively used for treatment of neuropsychiatric disorders.…”

β-elemene enhances anticancer and anti-metastatic effects of osteosarcoma of ligustrazine in�vitro and in�vivo

“…However, recently, there are many evidences by many different studies shows that TIMP-1 is a kind of multifunctional protein. In addition of inhibiting MMP activity, it also has the unique function to stimulate tumor, participating in the process of cell apoptosis, cell proliferation and tumor angiogenesis etc., which has explained the mechanism to hint the poor prognosis in the breast cancer with its increased content (27). In addition of inhibiting MMP hydrolytic activity, it also has the unique cytokine-like function, capable of participating in the proliferation, apoptosis of tumor cell and tumor angiogenesis through signal transduction pathway (28).…”