Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-α inhibitor

Clements, John M.; Cossins, Judy; Wells, Graham; Corkill, Dominic J.; Helfrich, Karen; Wood, LM; Pigott, Rod; Stabler, G.; Ward, George A.; Gearing, A. J. H.; Miller, Karen

doi:10.1016/s0165-5728(96)00210-x

Cited by 203 publications

(140 citation statements)

References 38 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…Supporting findings in MS patients, the induction or enhanced expression of several MMP family members has been linked to promotion of disease in animal models of MS [48,130]. For example, MMP-9 is elevated in brain of EAE mice [48,201], and MMP-9-deficient young mice are resistant to EAE development [68].…”

Section: Matrix Metalloproteasesmentioning

confidence: 99%

“…Matrix metalloproteases (MMPs) have received most attention regarding their role in MS pathogenesis [298], and in experimental models of MS including experimental autoimmune encephalomyelitis (EAE) [48,265,288] and Theiler's murine encephalomyelitis virus (TMEV) [273] (Table 1 ). MMPs make up an expanding family of enzymes with a zincbinding motif that degrade and remodel structural proteins in the extracellular matrix (ECM), such as collagens, aggrecan, fibronectin, and laminin.…”

Section: Matrix Metalloproteasesmentioning

confidence: 99%

See 1 more Smart Citation

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Scarisbrick

2008

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases.

show abstract

Section: Matrix Metalloproteasesmentioning

confidence: 99%

Section: Matrix Metalloproteasesmentioning

confidence: 99%

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Scarisbrick

2008

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

show abstract

“…TIMP-2 blocked the MMP-2-induced BBB opening in MMPinduced injury in the brain (Rosenberg et al, 1992). Damage to the BBB was blocked, and symptomatic improvement occurred in experimental allergic encephalomyelitis (EAE) with hydroxymate treatment (Gijbels et al, 1994;Hewson et al, 1995;Clements et al, 1997). BB-94 blocked the BBB opening after intracerebral injection of TNF-␣, and BB-1101 was effective in LPS-induced BBB injury MunBryce and Rosenberg,1998a).…”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

778

667

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders. GLIA 39: 279 -291, 2002.

show abstract

“…MMPs are believed to play a critical role in immune cell extravasation into the CNS through the blood-brain barrier (BBB). Interestingly, the expression of various MMPs is increased in MS [10,31] and EAE [8]. Inhibitors of MMP also block the development of EAE [4,17,22].…”

Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses.Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-α that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS.Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ 2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ 2 is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ 2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ 2 and 9-cis RA inhibit cell activation through the formation of PPAR-γ/ RXR heterodimers. Interestingly, PGA 2 , which like 15d-PGJ 2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ 2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ 2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ 2 in combination with retinoids may be effective in the treatment of MS.

show abstract

Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-α inhibitor

Cited by 203 publications

References 38 publications

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Matrix metalloproteinases in neuroinflammation

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Contact Info

Product

Resources

About