Matrix MetalloProteinases, Tumor Necrosis Factor And Multiple Sclerosis: An Overview
Chandler S, Miller KM, Clements JM, Lury J, Corkill D, Anthony DC, Adams SE, Gearing AJ
J NeuroImmunol 1997 Feb;72(2):155-61
British Biotech Pharmaceuticals Limited, Cowley, Oxford, UK
PMID# 9042108; UI# 97194670
The Matrix MetalloProteinases (MMPs) are a family of at least 14 Zinc-dependent Enzymes which are known to degrade the protein components of ExtraCellular Matrix.
In addition, MMPs and related Enzymes can also process a number of cell surface Cytokines, receptors, and other soluble proteins.
In particular we have shown that the release of the pro-inflammatory Cytokine, Tumor Necrosis Factor-, from its membrane-bound precursor is an MMP-dependent process.
MMPs are expressed by the inflammatory cells which are associated with CNS Lesions in animal models of Multiple Sclerosis (MS) and in tissue from patients with the disease.
MMP expression will contribute to the tissue destruction and inflammation in MS. Drugs which inhibit MMP activity are effective in animal models of MS and may prove to be useful therapies in the clinic.
Effect Of Steroids On CSF Matrix MetalloProteinases In Multiple Sclerosis: Relation To Blood-Brain Barrier Injury
Rosenberg GA, Dencoff JE, Correa N Jr, Reiners M, Ford CC
Neurology 1996 Jun;46(6):1626-32
Univ of New Mexico, School of Medicine, Dept of Neurology, Albuquerque, USA
PMID# 8649561; UI# 96248980
Contrast-enhanced MRI in patients with MS shows that increased permeability of the Blood-Brain Barrier (BBB) commonly occurs. The changes in Capillary permeability often precede T2-weighted MRI evidence of tissue damage.
In animal studies, IntraCerebral injection of the Matrix MetalloProteinase (MMP) 72-kDa type IV Collagenase (Gelatinase A) opens the BBB by disrupting the Basal Lamina around Capillaries.
Steroids affect production of endogenous MMPs and Tissue Inhibitors to MetalloProteinases (TIMPs).
To determine the role of MMP activity in BBB damage during acute exacerbations of MS, we measured MMPs in the CSF of patients with MS.
Patients (n = 7) given Steroids to treat an acute episode of MS had CSF sampled before and after 3 days of MethylPrednisolone (1 g/day).
Patients had a graded Neurologic Examination and Gadolinium-enhanced MRI before treatment. CSF studies included total protein, cell count, and a DeMyelinating profile.
We measured levels of MMPs, Urokinase-type PlasMinogen Activator (uPA), and TIMPs by Zymography, Reverse Zymography, and Western blots.
The MMP, 92-kDa type IV Collagenase (Gelatinase B), fell from 216 +/- 70 before Steroids to 54 +/- 26 relative lysis zone units (p < 0.046) after treatment. Similarly, uPA dropped from 3880 +/- 800 to 2655 +/- 353 (p < 0.03).
Four patients with Gadolinium enhancement on MRI had the most pronounced drop in Gelatinase B and uPA.
Western Immunoblots showed an increase in a complex of Gelatinase B and TIMPs after treatment, suggesting an increase in a TIMP (p < 0.05).
Reverse Zymography of CSF samples showed that Steroids increased a TIMP with a molecular weight similar to that of mouse TIMP-3 (p = 0.053).
Our results suggest that increased Gelatinase B is associated with an open BBB on MRI.
Steroids may improve Capillary function by reducing activity of Gelatinase B and uPA and increasing levels of TIMPs.
Matrix MetalloProteinases In The Normal Human Central Nervous System, Microglial Nodules, And Multiple Sclerosis Lesions
Maeda A, Sobel RA
J NeuroPathol Exp Neurol 1996 Mar;55(3):300-9
Veterans Administration Medical Center, Pathology and Laboratory Services, Palo Alto, California, USA
PMID# 8786388; UI# 96207825
Matrix MetalloProteinases (MMPs) comprise a family of ProteoLytic enzymes that are involved in remodeling of the ExtraCellular Matrix (ECM) of many tissues.
They have been implicated in degradation of Vascular basement membranes thereby facilitating Leukocyte migration into inflammatory sites.
To determine the cellular localization and levels of MMPs in the normal human Central Nervous System (CNS), Multiple Sclerosis (MS) lesions, and other conditions, cryostat sections of CNS samples were Immunostained with AntiSera to MMP-1, -2, -3 and -9.
In control White Matter the principal cells that express the MMPs were PeriVascular and Parenchymal Microglia.
Cellular MMP expression was also found in sporadic Microglial nodules in MS White Matter. Most CNS MicroVessel Endothelial Cells expressed MMP-3 and -9 but not MMP-1 or -2.
The majority of Macrophages in active MS and Necrotic lesions were MMP-l-, -2-, -3-, and -9-positive whereas chronic MS lesions had fewer MMP-positive Macrophages.
Small numbers of Astrocytes were MMP-2-, -3- and -9-positive in acute and chronic MS lesions.
These data suggest that Microglia-derived MMPs may mediate turnover of the CNS ECM under normal conditions and in Microglial nodules.
In sites of CNS tissue injury there is complex and dynamic regulation of MMP expression by different cell populations.
In MS lesions MMP-mediated ProteoLysis may contribute to breakdown of the Blood-Brain Barrier and Leukocyte migration into the CNS.
In situ Immune activation, DeMyelination, metabolism of bioactive Peptides, and the formation of an ECM that does not promote ReMyelination or Axonal repair.
ExtraCellular Matrix-Degrading Proteinases In The Nervous System
Romanic AM, Madri JA
Brain Pathol 1994 Apr;4(2):145-56
Yale Univ, School of Medicine, Dept of Pathology, New Haven, CT 06510
PMID# 8061860; UI# 94340129
The ProteoLytic activities of Matrix MetalloProteinases and PlasMinogen Activators as well as their inhibitors are important in maintaining the integrity of the ExtraCellular Matrix (ECM).
Cell-ECM interactions influence cell proliferation, differentiation, adhesion and migration.
In the Nervous System, ProteoLysis of the ECM is involved in Neuronal Cell migration in the developing Cerebellum and in Neurite outgrowth.
Likewise, in pathological conditions such as Brain Tumor growth and invasion, Leukocyte infiltration into Brain Tumors, Leukocyte trafficking in the Central Nervous System in inflammatory diseases such as Multiple Sclerosis and Viral Encephalitis.
And in Nerve DeMyelination, Matrix-degrading Proteinases and their inhibitors have been implicated.
An understanding of Cell-ECM interactions and ECM degradation in diseases of the Nervous System would provide new insight for drug design and other forms of therapy.
CerebroSpinal Fluid And Serum Levels And Intrathecal Production Of Active Matrix MetalloProteinase-9 (MMP-9) As Markers Of Disease Activity In Patients With Multiple Sclerosis
Fainardi E, Castellazzi M, Bellini T, Manfrinato MC, Baldi E, Casetta I, Paolino E, Granieri E, Dallocchio F
Mult Scler 2006 Jun;12(3):294-301
University of Ferrara, Multiple Sclerosis Center, Section of Neurology, Arcispedale S. Anna, Corso della Giovecca 203, Ferrara 1-44100, Italy
In this study, we employed a sensitive activity assay system to measure CerebroSpinal Fluid (CSF) and Serum levels of active Matrix MetalloProteinase-9 (MMP-9) in 37 Relapsing/Remitting (RR), 15 Secondary/Progressive (SP) and nine Primary/Progressive (PP) Multiple Sclerosis (MS) patients
Grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity.
We also studied, as Neurological controls, 48 patients with Other Inflammatory Neurological Disorders (OIND) and 48 with Non-Inflammatory Neurological Disorders (NIND).
To assess active MMP-9/TIMP-1 circuit, CSF and Serum levels of MMP-9 Tissue Inhibitor TIMP-1 were quantified by ELISA in the same patient population.
CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and Intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P < 0.05, < 0.02 and < 0.02, respectively).
Serum active MMP-9/TIMP-1 ratio was higher in MS (P < 0.01) and OIND (P < 0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P < 0.05).
More importantly, Serum active MMP-9 mean levels, serum active MMP-9/TIMP-1 ratio and intrathecal production of active MMP-9 were increased in MS patients with clinical (P < 0.001, < 0.001 and < 0.05, respectively) and MRI (P < 0.001, < 0.001 and < 0.02, respectively) disease activity.
Whereas CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P < 0.02 and < 0.01, respectively).
Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS Immune dysregulation.
In addition, our results indicate that CSF and Serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity.
In particular, Serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.