Sage Journals: Discover world-class research

Abstract

Background

A recent proteomics study of multiple sclerosis (MS) lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination. However, among thousands of proteins examined, nearly all of remaining proteins are yet to be characterized in terms of their implications in MS brain-lesion development.

Methods

By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaques, chronic active plaques (CAP), and chronic plaques (CP).

Results

The database search on Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER) indicated the relevance of extracellular matrix (ECM)–mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain-lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Ingenuity pathway analysis (IPA) identified the network constructed with a wide range of ECM components, such as collagen, type I α1, type I α2, type VI α2, type VI α3, fibronectin 1, fibulin 2, laminin α1, vitronectin, and heparan sulfate proteoglycan, as one of the networks highly relevant to CAP proteome.

Conclusions

Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These in silico observations indicate that the selective blockade of the interaction between ECM and integrins in brain lesions in situ would be a target for therapeutic intervention in MS.

Keywords

extracellular matrix multiple sclerosis pathway analysis proteome systems biology

Get full access to this article

View all access options for this article.

References

1 Lassmann H Brück W Lucchinetti CF . The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007; 17: 210–218.

2 Kieseier BC Wiendl H Hemmer B Hartung HP . Treatment and treatment trials in multiple sclerosis. Curr Opin Neurol 2007; 20: 286–293.

3 Kingsmore SF Lindquist IE Mudge J Gessler DD Beavis WD . Genome-wide association studies: progress and potential for drug discovery and development. Nat Rev Drug Discov 2008; 7: 221–230.

4 Steinman L Zamvil S . Transcriptional analysis of targets in multiple sclerosis. Nat Rev Immunol 2003; 3: 483–492.

5 Quintana FJ Farez MF Weiner HL . Systems biology approaches for the study of multiple sclerosis. J Cell Mol Med 2008; doi 10.1111/j.1582-4934.2008.00375.x.

6 Lock C Hermans G Pedotti R . Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002; 8: 500–508.

7 Satoh J Nakanishi M Koike F . Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis. Neurobiol Dis 2005; 18: 537–550.

8 Han MH Hwang SI Roy DB . Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451: 1076–1081.

9 Ganter B Giroux CN . Emerging applications of network and pathway analysis in drug discovery and development. Curr Opin Drug Discov Devel 2008; 11: 86–94.

10.

10 Viswanathan GA Seto J Patil S Nudelman G Sealfon SC . Getting started in biological pathway construction and analysis. PLoS Comput Biol 2008; 4: e16.

11.

11 Albert R Jeong H Barabasi AL . Error and attack tolerance of complex networks. Nature 2000; 406: 378–382.

12.

12 Kanehisa M Araki M Goto S . KEGG for linking genomes to life and the environment. Nucleic Acids Res 2008; 36: D480–D484.

13.

13 Mi H Guo N Kejariwal A Thomas PD . PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways. Nucleic Acids Res 2007; 35: D247–D252.

14.

14 Palacios R Goni J Martinez-Forero I . A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases. PLoS ONE 2007; 2: e1222.

15.

15 Sato H Ishida S Toda K . New approaches to mechanism analysis for drug discovery using DNA microarray data combined with KeyMolnet. Curr Drug Discov Technol 2005; 2: 89–98.

16.

16 Luo BH Carman CV Springer TA . Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25: 619–647.

17.

17 Sobel RA . The extracellular matrix in multiple sclerosis lesions. J Neuropathol Exp Neurol 1998; 57: 205–217.

18.

18 van Horssen J Dijkstra CD de Vries HE . The extracellular matrix in multiple sclerosis pathology. J Neurochem 2007; 103: 1293–1301.

19.

19 Sobel RA Chen M Maeda A Hinojoza JR . Vitronectin and integrin vitronectin receptor localization in multiple sclerosis lesions. J Neuropathol Exp Neurol 1995; 54: 202–213.

20.

20 Minagar A Jy W Jimenez JJ . Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 2001; 56: 1319–1324.

21.

21 Milner R Huang X Wu J . Distinct roles for astrocyte αvβ5 and αvβ8 integrins in adhesion and migration. J Cell Sci 1999; 112: 4271–4279.

22.

22 Sobel RA Mitchell ME . Fibronectin in multiple sclerosis lesions. Am J Pathol 1989; 135: 161–168.

23.

23 Sisková Z Baron W de Vries H Hoekstra D . Fibronectin impedes “myelin” sheet-directed flow in oligodendrocytes: a role for a beta 1 integrin-mediated PKC signaling pathway in vesicular trafficking. Mol Cell Neurosci 2006; 33: 150–159.

24.

24 Milner R Crocker SJ Hung S Wang X Frausto RF del Zoppo GJ . Fibronectin- and vitronectin-induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins α5β1 and αvβ5. J Immunol 2007; 178: 8158–8167.

25.

25 Ren Y Savill J . Proinflammatory cytokines potentiate thrombospondin-mediated phagocytosis of neutrophils undergoing apoptosis. J Immunol 1995; 154: 2366–2374.

26.

26 Chabas D Baranzini SE Mitchell D . The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001; 294: 1731–1735.

27.

27 Sinclair C Kirk J Herron B Fitzgerald U McQuaid S . Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 2007; 113: 187–194.

28.

28 Vogt MH Lopatinskaya L Smits M Polman CH Nagelkerken L . Elevated osteopontin levels in active relapsing-remitting multiple sclerosis. Ann Neurol 2003; 53: 819–822.

29.

29 Liu TJ LaFortune T Honda T . Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther 2007; 6: 1357–1367.

30.

30 Swenson S Costa F Minea R . Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Mol Cancer Ther 2004; 3: 499–511.

31.

31 Cantor JM Ginsberg MH Rose DM . Integrin-associated proteins as potential therapeutic targets. Immunol Rev 2008; 223: 236–251.

32.

32 Steinman L . Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 2005; 4: 510–518.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.13 MB