MMP-9

From MyWiki
Revision as of 16:23, 13 November 2017 by Rmattila (talk | contribs)
Jump to: navigation, search

Key concepts in ALS

MMP-9 in ALS

Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001, p=0.03, respectively). We observed CSF MMP-9 to be highest in patients with a rapid progressive course of disease (p=0.008). In contrast, we found no significant differences of CSF, serum or skin concentrations of MMP-2 as compared to controls. CSF MMP-2 concentrations decreased with duration of disease (p=0.04, R=-0.31). MDA was elevated in serum of ALS (p<0.001), though no correlation with MMP-2 or MMP-9 was observed. Our findings indicate a general upregulation of MMP-9 in ALS. MMP-9 seems to play a role in both neurodegeneration and skin changes in ALS and could thus be a common factor linking otherwise distant aspects of disease pathology. [1]

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. [2]

Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(-1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(-1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(-1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506-3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95% CI 1.233-3.796, p = 0.006), supporting a role for MMP-9 polymorphism in the risk for PD and sALS. [3]

Inhibition

Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood-brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia. [4]

References

  1. Fang et al.: Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS). J. Neurol. Sci. 2009;285:62-6. PMID: 19523650. DOI. Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001, p=0.03, respectively). We observed CSF MMP-9 to be highest in patients with a rapid progressive course of disease (p=0.008). In contrast, we found no significant differences of CSF, serum or skin concentrations of MMP-2 as compared to controls. CSF MMP-2 concentrations decreased with duration of disease (p=0.04, R=-0.31). MDA was elevated in serum of ALS (p<0.001), though no correlation with MMP-2 or MMP-9 was observed. Our findings indicate a general upregulation of MMP-9 in ALS. MMP-9 seems to play a role in both neurodegeneration and skin changes in ALS and could thus be a common factor linking otherwise distant aspects of disease pathology.
  2. Kaplan et al.: Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron 2014;81:333-48. PMID: 24462097. DOI. 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.
  3. He et al.: Association studies of MMP-9 in Parkinson's disease and amyotrophic lateral sclerosis. PLoS ONE 2013;8:e73777. PMID: 24040066. DOI. Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(-1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(-1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(-1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506-3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95% CI 1.233-3.796, p = 0.006), supporting a role for MMP-9 polymorphism in the risk for PD and sALS.
  4. Chaturvedi & Kaczmarek: Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol. Neurobiol. 2014;49:563-73. PMID: 24026771. DOI. Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood-brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia.