Potential relevance of cerebrospinal fluid and serum levels and intrathecal synthesis of active matrix metalloproteinase-2 (MMP-2) as markers of disease remission in patients with multiple sclerosis

Abstract

Background

Little is known about the involvement of matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor TIMP-2 in multiple sclerosis (MS).

Objective

To elucidate the actual implication of MMP-2 and TIMP-2 in MS.

Methods

Cerebrospinal fluid (CSF) and serum levels of active MMP-2 and TIMP-2 were measured by activity assay system and ELISA, respectively, in 67 patients with relapsing–remitting MS (RRMS), categorized according clinical and magnetic resonance imaging (MRI), and in 129 controls.

Results

Cerebrospinal fluid and serum active MMP-2/TIMP-2 ratio mean values and an intrathecal active MMP-2 production were more increased in RRMS than in non-inflammatory conditions (P < 0.001, P < 0.05, and P < 0.0001, respectively) and in MRI inactive than in MRI active RRMS (P < 0.02, P < 0.01 and P < 0.001, respectively). An intrathecal synthesis of active MMP-2 was more frequent in RRMS than in inflammatory disorders (P < 0.01). Serum active MMP-2/TIMP-2 ratio and MS disease duration were positively correlated (P < 0.02).

Conclusion

These findings suggest a potential role for MMP-2 activity in the termination of MS neuroinflammation related to remission of the disease and seem to indicate that serum MMP-2/TIMP-2 ratio may represent a useful biomarker for monitoring MS recovery phase.

Keywords

cerebrospinal fluid intrathecal synthesis MMP-2 multiple sclerosis TIMP-2

Get full access to this article

View all access options for this article.

References

1 Sospedra M Martin R . Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747.

2 Yong VW . Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 2005; 6: 931–944.

3 Yong VW Zabad RK Agrawal S . Goncalves DaSilva, A, Metz, LM. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci 2007; 259: 79–84.

4 Fainardi E Castellazzi M Bellini T . Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Mult Scler 2006; 12: 294–301.

5 Rosenberg GA . Matrix metalloproteinases in neuroinflammation. Glia 2002; 39: 279–291.

6 Anthony DC Ferguson B Matyzak MK Miller KM Esiri MM Perry VH . Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol Appl Neurobiol 1997; 23: 403–415.

7 Diaz-Sanchez M Williams K De Luca GC Esiri MM . Protein co-expression with axonal injury in multiple sclerosis plaques. Acta Neuropathol 2006; 111: 289–299.

8 Lindberg RL De Groot CJA Montagne L . The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis. Brain 2001; 124: 1743–1753.

9 Rosenberg GA Dencof JE Correa N Reiners M Ford CC . Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis. Relation to blood-brain barrier injury. Neurology 1996; 46: 1696–1632.

10.

10 Leppert D Ford J Stabler G . Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 1998; 121: 2327–2334.

11.

11 Mandler RN Dencoff JD Midani F Ford CC Ahmed W Rosenberg GA . Matrix metalloproteinases and tissue inhibitors of metalloproteinases in cerebrospinal fluid differ in multiple sclerosis and Devic’s neuromyelitis optica. Brain 2001; 124: 493–498.

12.

12 Avolio C Ruggieri M Giuliani F . Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes. J Neuroimmunol 2003; 136: 46–53.

13.

13 Lee MA Palace J Stabler G Ford J Gearing A Miller K . Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain 1999; 122: 191–197.

14.

14 Correale J Bassani Molinas Mde L . Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS. J Neuroimmunol 2003; 140: 198–209.

15.

15 Kouwenhoven M Özenci V Tjernlund A . Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis. J Neuroimmunol 2002; 126: 161–171.

16.

16 Bar-Or A Nuttall RK Duddy M . Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 2003; 126: 2738–2749.

17.

17 Abraham M Shapiro S Karni A Wiener HL Miller A . Gelatinases (MMP-2 and MMP-9) are preferentially expressed by Th1 vs. Th2 cells. J Neuroimmunol 2005; 163: 157–164.

18.

18 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50: 121–127.

19.

19 Lublin DF Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–911.

20.

20 Poser CM Paty DW Scheimberger L . New diagnostic criteria for MS: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

21.

21 Kurtzke JF . Rating neurological impairment in multiple sclerosis: an expanded disability scale (EDSS). Neurology 1983; 33: 1444–1452.

22.

22 Salden HJM Bas BM Hermas JT Janson PC . Analytical performance of the three commercially available nephelometers compared quantifying protein in serum and cerebrospinal fluid. Clin Chem 1988; 34: 1594–1596.

23.

23 Tibbling G Link H Ohman S . Principles of albumin and IgG analyses in neurological disorders: I. Establishment of reference value. Scand J Clin Lab Invest 1977; 37: 385–390.

24.

24 Miller DH Barkhof F Nauta JJP . Gadolinium enhancement increases the sensitivity of MRI in detecting disease activity in multiple sclerosis. Brain 1993; 116: 1077–1094.

25.

25 Esparza J Kruse M Lee J Michaud M Madri JA . MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. FASEB J 2004; 18: 1682–1691.

26.

26 McQuibban A Gong JH Wong JP Wallace JL Clark-Lewis I Overall CM . Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002; 100: 1160–1167.

27.

27 Bever CT Rosenberg GA . Matrix metalloproteinases in multiple sclerosis. Targets of therapy or markers of injury? Neurology 1999; 53: 1380–1381.

28.

28 Bielekova B Martin R . Development of biomarkers in multiple sclerosis. Brain 2004; 127: 1463–1478.

29.

29 Gerlach RF Uzuelli JA Souza-Tarla CD Tanus-Santos JE . Effect of anticoagulants on the determination of plasma matrix metalloproteinase (MMP)-2 and MMP-9 activities. Anal Biochem 2005; 344: 147–149.

30.

30 Castellazzi M Tamborino C Fainardi E . Effects of anticoagulants on the activity of gelatinases. Clin Biochem 2007; 40: 1272–1276.