Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

https://journals.sagepub.com/doi/pdf/10.1177/0271678X16655551

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers:

Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models.

Human matrix metalloproteinases: an ubiquitarian class of enzymes involved in several pathological processes.

Cardiovascular disease is the leading cause of death, accounting for 600,000 deaths each year in the United States. In addition, heart failure accounts for 37% of health care spending. Matrix metalloproteinases (MMPs) increase after myocardial infarction (MI) and correlate with left ventricular dysfunction in heart failure patients. MMPs regulate the remodeling process by facilitating extracellular matrix turnover and inflammatory signaling. Due to the critical role MMPs play during cardiac remodeling, there is a need to better understand the pathophysiological mechanism of MMPs, including the biological function of the downstream products of MMP proteolysis. Future studies developing new therapeutic targets that inhibit specific MMP actions to limit the development of heart failure post-MI are warranted. This chapter focuses on the role of MMPs post-MI, the efficiency of MMPs as biomarkers for MI or heart failure, and the future of MMPs and their cleavage products as targets for prevention of post-MI heart failure.

Matrix Metalloproteinases in Myocardial Infarction and Heart Failure.

Cell Culture Media: A Review

Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Metalloproteinases are important mediators in the development of the nervous system and can contribute to the maturation of the neural micro-environment. MMP-28 added to myelinating rat dorsal root ganglion (DRG) co-cultures reduces myelination and two antibodies targeted to MMP-28 (pAb180 and pAb183) are capable of binding MMP-28 and inhibiting its activity in a dose-dependent manner. Addition of 30 nM pAb180 or pAb183 to rat DRG cultures resulted in the 2.6 and 4.8 fold enhancement of myelination respectively while addition of MMP-28 to DRG co-cultures resulted in enhanced MAPK, ErbB2 and ErbB3 phosphorylation. MMP-28 protein expression was increased within demyelinated lesions of mouse experimental autoimmune encephalitis (EAE) and human multiple sclerosis lesions compared to surrounding normal tissue. MMP-28 is upregulated in conditions of demyelination in vivo, induces signaling in vitro consistent with myelination inhibition and, neutralization of MMP-28 activity can enhance myelination in vitro. These results suggest inhibition of MMP-28 may be beneficial under conditions of dysmyelination.

/pdf/mmp-28-as-a-regulator-of-myelination-4lldw1p3j6.pdf

MMP-28 as a regulator of myelination

Mammalian matrix metalloproteinase 28 (MMP-28) is expressed in several normal adult tissues, and during cutaneous wound healing. We show that, in frog and mouse embryos, MMP-28 is expressed predominantly throughout the nervous system. Xenopus expression increases during neurulation and remains elevated through early limb development where it is expressed in nerves. In the mouse, neural expression peaks at embryonic day (E) 14 but remains detectable through E17. During frog hindlimb regeneration XMMP-28 is not initially expressed in the regenerating nerves but is detectable before myelination. Following hindlimb denervation, XMMP-28 expression is detectable along regenerating nerves before myelination. In embryonic rat neuron–glial co-cultures, MMP-28 decreases after the initiation of myelination. Incubation of embryonic brain tissue with purified MMP-28 leads to the degradation of multiple myelin proteins. These results suggest that MMP-28 plays an evolutionarily conserved role in neural development and is likely to modulate the axonal–glial extracellular microenvironment. Developmental Dynamics 236:2852–2864, 2007. © 2007 Wiley-Liss, Inc.

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/dvdy.21301

Neural MMP-28 expression precedes myelination during development and peripheral nerve repair.

Cuprizone intoxication is a commonly used model of demyelination that allows the temporal separation of demyelination and remyelination. The underlying biochemical alterations leading to demyelination, using this model, remain unclear and may be multifold. Analysis of proteomic changes within the brains of cuprizone-exposed animals may help elucidate key cellular processes. In the current study, we report the results of the liquid chromatography tandem mass spectrometry analysis of total protein from the brain hemispheres of control and toxin-exposed mice at 6 weeks of exposure and after 3 and 6 weeks of recovery to identify protein changes during the remyelination phase. We found that at 6 weeks of cuprizone exposure, myelin proteins were reduced compared to controls and increased throughout the course of recovery, as expected. In contrast, other protein groups, such as proteins related to mitochondrial function, were increased at 6 weeks of treatment compared to untreated controls and returned toward control levels following withdrawal of toxin. These results suggest that a global proteomic analysis of the brain tissue of cuprizone-treated mice can identify changes related to the demyelination/remyelination process.

Proteomic analysis of demyelinated and remyelinating brain tissue following dietary cuprizone administration.

The present invention relates to the use of an MMP28 inhibitor, e.g., an anti-MMP28 antibody, to increase myelination. The methods of the present invention are accomplished by administering an MMP28 inhibitor to a subject having a demyelination or insufficient myelination disease, disorder or condition.

Use of an mmp28 inhibitor for increasing myelination

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MMP-28 as a regulator of myelination

Neural MMP-28 expression precedes myelination during development and peripheral nerve repair.

Proteomic analysis of demyelinated and remyelinating brain tissue following dietary cuprizone administration.

Use of an mmp28 inhibitor for increasing myelination