Increased osteopontin plasma levels in multiple sclerosis patients correlate with bone-specific markers

Abstract

The pro-inflammatory cytokine osteopontin has been found to be highly expressed in multiple sclerosis lesions and plasma levels are increased during relapses in relapse-onset multiple sclerosis patients.

The objective was to determine the relationship between osteopontin plasma and cerebrospinal fluid levels in relation to the immunoglobulin G index. In addition, osteopontin plasma levels were compared with osteopontin mRNA levels in peripheral blood mononuclear cells and bone-specific markers to analyse whether osteopontin may be peripherally produced.

Osteopontin and bone-specific markers were determined in paired plasma—cerebrospinal fluid samples and serum samples of relapse-onset multiple sclerosis patients (n = 36), respectively. Osteopontin mRNA levels were determined by quantitative polymerase chain reaction analysis.

Compared to healthy controls (n = 20), plasma osteopontin levels were significantly increased in relapsing-remitting multiple sclerosis patients and correlated (r = 0.43, p = 0.013) with the immunoglobulin G index. In contrast, cerebrospinal fluid osteopontin levels correlated neither with plasma osteopontin in paired samples nor with the immunoglobulin G index. Since osteopontin mRNA levels in peripheral blood mononuclear cells of relapsing-remitting multiple sclerosis patients did not correlate with osteopontin plasma levels, peripheral blood mononuclear cells might not be the major source for the increased osteopontin plasma levels. Osteopontin plasma levels correlated (r = 0.42, p = 0.035) with the bone-specific degradation product C-telopeptide of type-1 collagen. In addition, another immunomodulatory molecule involved in bone metabolism, 25-OH vitamin D, correlated negatively (r = —0.359, p = 0.048) with the immunoglobulin G index.

This study suggests that bone-related molecules like osteopontin and vitamin D with important immunomodulatory functions are related to the immunoglobulin G index in relapsing-remitting multiple sclerosis patients.

Keywords

Multiple sclerosis osteopontin bone

Get full access to this article

View all access options for this article.

References

Steinman L. A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol 2009; 9: 440-447.

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

Vogt MH , Lopatinskaya L. , Smits M. , et al. Elevated osteopontin levels in active relapsing-remitting multiple sclerosis. Ann Neurol 2003; 53: 819-822.

Comabella M. , Pericot I. , Goertsches R. , et al. Plasma osteopontin levels in multiple sclerosis. J Neuroimmunol 2005; 158: 231-239.

Vogt MH , Floris S. , Killestein J. , et al. Osteopontin levels and increased disease activity in relapsing-remitting multiple sclerosis patients. J Neuroimmunol 2004; 155: 155-160.

Chowdhury SA , Lin J. , Sadiq SA Specificity and correlation with disease activity of cerebrospinal fluid osteopontin levels in patients with multiple sclerosis . Arch Neurol 2008 ; 65: 232-235.

Braitch M. , Nunan R. , Niepel G. , et al. Increased osteopontin levels in the cerebrospinal fluid of patients with multiple sclerosis. Arch Neurol 2008; 65: 633-635.

Qin C. , Baba O. , Butler WT Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med 2004; 15: 126-136.

Ross FP , Chappel J. , Alvarez JI , et al. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem 1993; 268: 9901-9907.

10.

Asou Y. , Rittling SR , Yoshitake H. , et al. Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone. Endocrinology 2001; 142: 1325-1332.

11.

Mazzali M. , Kipari T. , Ophascharoensuk V. , et al. Osteopontin-a molecule for all seasons. QJM 2002; 95: 3-13.

12.

Denhardt DT , Noda M. , O’Regan AW , et al. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 2001; 107: 1055-1061.

13.

Ashkar S. , Weber GF , Panoutsakopoulou V. , et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000; 287: 860-864.

14.

Hur EM , Youssef S. , Haws ME , et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 2007; 8: 74-83.

15.

Murugaiyan G. , Mittal A. , Weiner HL Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis. J Immunol 2008; 181: 7480-7488.

16.

Patarca R. , Freeman GJ , Singh RP , et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J Exp Med 1989; 170: 145-161.

17.

O’Regan A. , Berman JS Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol 2000; 81: 373-390.

18.

McDonald WI , Compston A. , Edan G. , et al. Recommended criteria for multiple sclerosis: guidelines from the international Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121-127.

19.

Zhao C. , Fancy SP , ffrench-Constant C. , Franklin RJ Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiol Dis 2008; 31: 209-217.

20.

Lindberg RLP , Kappos L. Transcriptional profiling of multiple sclerosis: towards improved diagnosis and treatment. Expert Rev Mol Diagn 2006; 6: 843-855.

21.

Bomprezzi R. , Ringner M. , Kim S. , et al. Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum Mol Genet 2003; 12: 2191-2199.

22.

Tuzun S. , Altintas A. , Karacan I. , et al. Bone status in multiple sclerosis: beyond corticosteroids. Mult Scler 2003; 9: 600-604.

23.

Weinstock-Guttman B. , Gallagher E. , Baier M. , et al. Risk of bone loss in men with multiple sclerosis. Mult Scler 2004; 10: 170-175.

24.

Smolders J. , Menheere P. , Kessels A. , et al. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler 2008; 14: 1220-1224.

25.

Soilu-Hänninen M. , Laaksonen M. , Laitinen I. , et al. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008; 79: 152-157.

26.

Smolders J. , Damoiseaux J. , Menheere P. , et al. Vitamin D as an immune modulator in multiple sclerosis. J Neuroimmunol 2008; 194: 7-17.

27.

Rieckmann P. , Albrecht M. , Kitze B. , et al. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann Neurol 1995; 37: 82-88.

28.

Azuma Y. , Kaji K. , Katogi R. , et al. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 2000 ; 275: 4858-4864.

29.

Gravallese EM Osteopontin: a bridge between bone and the immune system. J Clin Invest 2003; 112: 147-149.

30.

Cheng X. , Kinosaki M. , Murali R. , Greene MI The TNF receptor superfamily: role in immune inflammation and bone formation . Immunol Res 2003; 27: 287-294.

31.

Nakashima T. , Takayanagi H. Osteoimmunology: crosstalk between the immune and bone systems. J Clin Immunol 2009; 29: 555-567.

32.

Zhu WH , Lu CZ , Huang YM , Link H. , Xiao BG A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2,3-dioxygenase by dendritic cells. Mult Scler 2007; 13: 33-40.

33.

Matarese G. , Carrieri PB , La Cava A. , et al. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A 2005; 102: 5150-5155.