Osteopontin levels and increased disease activity in relapsing–remitting multiple sclerosis patients M.H.J. Vogt a, * , S. Floris b , J. Killestein c , D.L. Knol d , M. Smits a , F. Barkhof e , C.H. Polman c , L. Nagelkerken a a Division of Biomedical Research, TNO Prevention and Health, P.O. Box 2215, 2301 CE Leiden, The Netherlands b Department of Molecular Cell biology, MS-MRI Center, VU Medical Center, Amsterdam, The Netherlands c Department of Neurology, MS-MRI Center, VU Medical Center, Amsterdam, The Netherlands d Department of Clinical Epidemiology and Biostatistics, MS-MRI Center, VU Medical Center, Amsterdam, The Netherlands e Department of Radiology, MS-MRI Center, VU Medical Center, Amsterdam, The Netherlands Received 11 June 2004; accepted 15 June 2004 Abstract Osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within multiple sclerosis (MS) lesions. Recently, we demonstrated that OPN plasma levels were elevated in active relapsing–remitting (RR) MS patients. In this longitudinal study, a trend was observed for OPN serum levels in relation to clinical exacerbations. Moreover, OPN protein levels were significantly elevated 1 month prior to increase of gadolinium (Gd)-enhancing lesion number, whereas no relation was observed between OPN levels and increase in Gd-enhancing lesion volume. Although no robust relation between OPN and disease activity was observed, these data suggest that OPN levels are elevated prior to increased disease activity in RR MS patients. D 2004 Elsevier B.V. All rights reserved. Keywords: Osteopontin; Disease activity; Relapsing–remitting multiple sclerosis 1. Introduction Multiple sclerosis (MS) is characterized by the presence of sclerotic lesions or plaques, scattered throughout the brain (Ewing and Bernard, 1998). Early events in the development of MS lesions are the formation of cellular infiltrates, consisting of monocyte-derived macrophages and T lymphocytes (Steinman et al., 2002; Neumann et al., 2002). Sequencing of cDNA from MS brain lesions and control brains has revealed that osteopontin (OPN) is the most abundant cytokine-encoding transcript unique to MS plaques (Chabas et al., 2001). Moreover, OPN protein levels are elevated in reactive astrocytes and microglial cells (Chabas et al., 2001). OPN is a negatively charged acidic hydrophilic protein of 314 amino acids and has pleiotropic functions, including a role in both acute and chronic inflammation (Mazzali et al., 2002; Gravallese, 2003). The interaction between the C- terminal domain of OPN and CD44 expressed by macro- phages results in the induction of chemotaxis and inhibits IL-10 production, whereas engagement of h3-integrin receptors by the N-terminal OPN domain induces activation and IL-12 production (Weber et al., 2002). The role of OPN in Th-1 responses has been confirmed in other studies as well. Mice deficient in OPN gene expression (OPN À/À ) have severely impaired type-1 immunity to viral and bacterial infections (Ashkar et al., 2000). Cells from draining lymph nodes from OPN À/À mice demonstrated impaired IL-12 and IFNg production and increased IL-10 production compared to OPN +/+ mice. Several studies demonstrated that a disturbed balance between pro- and anti-inflammatory cytokines at the mRNA 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2004.06.007 * Corresponding author. Tel.: +31 715181276; fax: +31 715181901. E-mail address: mhj.vogt@pg.tno.nl (M.H.J. Vogt). Journal of Neuroimmunology 155 (2004) 155 – 160 www.elsevier.com/locate/jneuroim