Matrix metalloproteinase-9 regulates TNF-α and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA. <>
Experimental Neurology (Impact Factor: 4.7). 06/2007; 205(1):74-81. DOI: 10.1016/j.expneurol.2007.01.036
Source: PubMed


Whether increased levels of matrix metalloproteinases (MMPs) correspond to a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) needs to be determined and it is actively being pursued. Here we present evidence suggesting that MMP-9 contributes to the motor neuron cell death in ALS. We examined the role of MMP-9 in a mouse model of familial ALS and found that lack of MMP-9 increased survival (31%) in G93A SOD1 mice. Also, MMP-9 deficiency in G93A mice significantly attenuated neuronal loss, and reduced neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord. These findings suggest that MMP-9 is an important player in the pathogenesis of ALS. Our data suggest that the mechanism for MMP-9 neurotoxicity in ALS may be by upregulating neuronal TNF-alpha and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.

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    • "This was increased to 178 days by removal of a single allele of Mmp9 and to 195 days by complete ablation, representing a 25% increase in lifespan (Figure 5L). Our survival data are comparable to those reported by Kiaei et al. (2007) (see Discussion) on a mixed background. The systemic benefit of MMP-9 deletion is clearly apparent from visual inspection of three male SOD1 G93A littermate mice bearing two, one, and zero copies of Mmp9 at P150 (Movie S1): even Mmp9 heterozygotes show major improvements in their ability to grasp bars and right themselves. "
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    ABSTRACT: Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration.
    Full-text · Article · Jan 2014 · Neuron
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    • "Pro-MMP-9 is elevated in the sera as well as in extracts of damaged nerve and muscle of ALS [92], which suggests that such damage might be followed by elevated pro-MMP-9 in sera. MMP-9 deficiency in G93A mice significantly attenuates neuronal loss, reduces neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord, and increases survival (31%) [93], which suggests that MMP-9 contributes to motor neuron cell death in ALS. Treatment with an MMP inhibitor starting at 30 days of age improved motor performance and significantly prolonged the survival time of the animals; however, administration at disease onset did not significantly improve the survival time [94]. "
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    ABSTRACT: Evidence suggests that there are aberrations in the vitamin D-endocrine system in subjects with amyotrophic lateral sclerosis (ALS). Here, we review the relationship between vitamin D and ALS. Vitamin D deficiency was reported in patients with ALS. Dietary vitamin D3 supplementation improves functional capacity in the G93A transgenic mouse model of ALS. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to ALS pathology, including major histocompatibility complex (MHC) class II molecules, toll-like receptors, poly(ADP-ribose) polymerase-1, heme oxygenase-1, and calcium-binding proteins, as well as the reduced form of nicotinamide adenine dinucleotide phosphate. Vitamin D also exerts its effect on ALS through cell-signaling mechanisms, including glutamate, matrix metalloproteinases, mitogen-activated protein kinase pathways, the Wnt/β-catenin signaling pathway, prostaglandins, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D may have a role in ALS. Further investigation of vitamin D in ALS patients is needed.
    Full-text · Article · Apr 2013 · Molecular Brain
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    • "Oral administration of 100 mg/kg broad spectrum MMP inhibitor Ro 26–2853 during the pre-symptomatic stage in transgenic SOD1 G93A mice with a high gene copy number improved motor function and significantly extended their survival time [18]. A recent study revealed a significant increase in the life span of MMP-9 ''knock-out " transgenic SOD1 G93A mice on a B6SJL background as well as a reduction of neuronal death in the spinal cord [19]. These studies suggest a pathogenic role of MMP-9 in the disease , and that inhibition of MMP-9 could be a potential therapeutic approach for treating ALS. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.
    Full-text · Article · Apr 2010 · Neuromuscular Disorders
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