Background:The cytokine osteopontin (OPN) is a potential key player in the immunopathogenesis of multiple sclerosis (MS) and a candidate biomarker for disease activity.
Objective:The objective of this study was to examine concentrations of OPN in the cerebrospinal fluid (CSF) across the clinical spectrum of MS.
Methods:Our research consisted of a cross-sectional study of patients from two randomized, placebo-controlled trials. Concentrations of OPN and other blood and CSF markers were determined using an enzyme-linked immunosorbent assay (ELISA). Samples were obtained from untreated patients with exacerbation of clinically isolated syndrome (CIS) (n = 25) and relapsing–remitting MS (RRMS) (n = 41) of whom 48 participated in clinical trials, randomly allocated to treatment with placebo or methylprednisolone (MP) and undergoing repeated sampling after 3 weeks. Furthermore, we obtained CSF and blood samples from patients with primary progressive MS (PPMS, n = 9), secondary progressive MS (SPMS, n = 28) and other neurological disorders (OND, n = 44), and blood samples from 24 healthy subjects.
Results:OPN concentrations were significantly increased in the CSF of patients with CIS (p = 0.02) and RRMS (p < 0.001) in exacerbation compared to patients with OND, and increased levels of OPN were associated with high values of other biomarkers of inflammation. At 3-week follow-up CSF OPN concentrations had decreased significantly from baseline regardless treatment with placebo or MP. Patients with PPMS had increased OPN levels in the CSF (p = 0.004) and high CSF levels of OPN were associated with high degrees of disability.
Conclusions:OPN concentration in the CSF is a dynamic indicator of disease activity in RRMS, presumably reflecting ongoing inflammation. Increased CSF OPN concentrations in PPMS may indicate ongoing inflammation even in these patients.
LassmannHBrückWLucchinettiCF. The immunopathology of multiple sclerosis: an overview. Brain Pathol2007; 17: 210–218.
2.
KutzelniggALucchinettiCFStadelmannC. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain2005; 128: 2705–2712.
3.
TrappBDNaveKA. Multiple sclerosis: an immune or neurodegenerative disorder?Annu Rev Neurosci2008; 31: 247–269.
4.
HolmøyTHestvikAL. Multiple sclerosis: immunopathogenesis and controversies in defining the cause. Curr Opin Infect Dis2008; 21: 271–278.
5.
FrischerJMBramowSDal-BiancoA. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain2009; 132: 1175–1189.
6.
MazzaliMKipariTOphascharoensukVWessonJAJohnsonRHughesJ. Osteopontin– ([a-z]+) molecule for all seasons. QJM2002; 95: 3–13.
7.
WangKXDenhardtDT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev2008; 19: 333–345.
8.
AshkarSWeberGFPanoutsakopoulouV. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science2000; 287: 860–864.
9.
NauGJGuilfoilePChuppGL. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci U S A1997; 94: 6414–6419.
10.
O'ReganAWHaydenJMBermanJS. Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells. J Leukoc Biol2000; 68: 495–502.
11.
ShinoharaMLKimJHGarciaVACantorH. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity2008; 29: 68–78.
12.
AspordCRomeSThivoletC. Early events in islets and pancreatic lymph nodes in autoimmune diabetes. J Autoimmun2004; 23: 27–35.
13.
ShinTAhnMKimHKimHMMatsumotoY. Increased expression of osteopontin in the heart tissue of Lewis rats with experimental autoimmune myocarditis. J Vet Med Sci2006; 68: 379–382.
14.
XuGNieHLiN. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest2005; 115: 1060–1067.
15.
WongCKLitLCTamLSLiEKLamCW. Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus. Rheumatology (Oxford)2005; 44: 602–606.
16.
SatoTNakaiTTamuraN. Osteopontin/Eta-1 upregulated in Crohn's disease regulates the Th1 immune response. Gut2005; 54: 1254–1262.
17.
ChabasDBaranziniSEMitchellD. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science2001; 294: 1731–1735.
18.
HurEMYoussefSHawsMEZhangSYSobelRASteinmanL. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol2007; 8: 74–83.
19.
MurugaiyanGMittalAWeinerHL. Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J Immunol2008; 181: 7480–7488.
20.
SinclairCMirakhurMKirkJFarrellMMcQuaidS. Up-regulation of osteopontin and alphaBeta-crystallin in the normal-appearing white matter of multiple sclerosis: an immunohistochemical study utilizing tissue microarrays. Neuropathol Appl Neurobiol2005; 31: 292–303.
21.
VogtMHLopatinskayaLSmitsMPolmanCHNagelkerkenL. Elevated osteopontin levels in active relapsing–remitting multiple sclerosis. Ann Neurol2003; 53: 819–822.
22.
VogtMHFlorisSKillesteinJ. Osteopontin levels and increased disease activity in relapsing–remitting multiple sclerosis patients. J Neuroimmunol2004; 155: 155–160.
AltintaşASaruhan-DireskeneliGBenbirGDemirMPurisaS. The role of osteopontin: a shared pathway in the pathogenesis of multiple sclerosis and osteoporosis?J Neurol Sci2009; 276: 41–44.
25.
ChowdhurySALinJSadiqSA. Specificity and correlation with disease activity of cerebrospinal fluid osteopontin levels in patients with multiple sclerosis. Arch Neurol2008; 65: 232–235.
26.
BraitchMNunanRNiepelGEdwardsLJConstantinescuCS. Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis. Arch Neurol2008; 65: 633–635.
27.
KhademiMBornsenLRafatniaF. The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers. Eur J Neurol2009; 16: 528–536.
28.
SellebjergFFrederiksenJLNielsenPMOlesenJ. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology1998; 51: 529–534.
29.
SellebjergFNielsenHSFrederiksenJLOlesenJ. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology1999; 52: 1479–1484.
30.
HoffmannGWirleitnerBFuchsD. Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm Res2003; 52: 313–321.
31.
WhitakerJN. Myelin basic protein in cerebrospinal fluid and other body fluids. Mult Scler1998; 4: 16–21.
32.
TerziMBirinciACetinkayaEOnarMK. Cerebrospinal fluid total tau protein levels in patients with multiple sclerosis. Acta Neurol Scand2007; 115: 325–330.
33.
SellebjergFChristiansenMJensenJFrederiksenJL. Immunological effects of oral high-dose methylprednisolone in acute optic neuritis and multiple sclerosis. Eur J Neurol2000; 7: 281–289.
34.
SellebjergFJensenCVLarssonHBFrederiksenJL. Gadolinium-enhanced magnetic resonance imaging predicts response to methylprednisolone in multiple sclerosis. Mult Scler2003; 9: 102–107.
35.
PatyDWOgerJJKastrukoffLF. MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology1988; 38: 180–185.
36.
KhademiMBornsenLRafatniaF. The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers. Eur J Neurol2009; 16: 528–536.
37.
KiddDThorpeJWKendallBE. MRI dynamics of brain and spinal cord in progressive multiple sclerosis. J Neurol Neurosurg Psychiatry1996; 60: 15–19.
38.
ThompsonAJKermodeAGWicksD. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol1991; 29: 53–62.
39.
PrineasJWKwonEEChoES. Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol2001; 50: 646–657.
40.
McFarlandHFMartinR. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol2007; 8: 913–919.
41.
SellebjergFBörnsenLKhademiM. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology2009; 73: 2003–2010.
BramowSFrisherJLaursenHKoch-HenriksenNLassmannH. Progressive multiple sclerosis: inflammatory demyelination correlates with the rate of clinical progression prior to death. Mult Scler2009; 15: S5–S29.
44.
ZhangQWranaJLSodekJ. Characterization of the promoter region of the porcine opn (osteopontin, secreted phosphoprotein 1) gene. Identification of positive and negative regulatory elements and a 'silent' second promoter. Eur J Biochem1992; 207: 649–659.
SinghKBalligandJLFischerTASmithTWKellyRA. Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. J Biol Chem1995; 270: 28471–28478.
47.
ChengSLZhangSFAvioliLV. Expression of bone matrix proteins during dexamethasone-induced mineralization of human bone marrow stromal cells. J Cell Biochem1996; 61: 182–193.
48.
LeeMNaSJeonDKimHChoiYBaikM. Induction of osteopontin gene expression during mammary gland involution and effects of glucocorticoid on its expression in mammary epithelial cells. Biosci Biotechnol Biochem2000; 64: 2225–2228.
49.
HakkiSSNohutcuRMHakkiEEBerryJEAkkayaMSSomermanMJ. Dexamethasone and basic-fibroblast growth factor regulate markers of mineralization in cementoblasts in vitro. J Periodontol2005; 76: 1550–1558.
50.
KirtonJPWilkinsonFLCanfieldAEAlexanderMY. Dexamethasone downregulates calcification-inhibitor molecules and accelerates osteogenic differentiation of vascular pericytes: implications for vascular calcification. Circ Res2006; 98: 1264–1272.
51.
WeinerHL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?Ann Neurol2009; 65: 239–248.
