Matrix Metalloproteinases in the Pathophysiology of Multiple Sclerosis

Authors: M. Hladíková;  P. Štourač
Authors‘ workplace: Neurologická klinika LF MU a FN Brno
Published in: Cesk Slov Neurol N 2008; 71/104(5): 530-536
Category: Review Article


The matrix metalloproteinases are a family of proteolytic enzymes which are known to degrade extracellular matrix. They participate in tissue remodelling in certain physiological and pathological conditions. They play an important role in the process of neuroinflammation, for example in multiple sclerosis. This review maps the state of present knowledge on the importance of the matrix metalloproteinases in the pathophysiology of multiple sclerosis, and it also points out possible uses of these findings in clinical practice.

Key words:
matrix metalloproteinases – multiple sclerosis – neuroinflammation – blood--brain barier – extracellular matrix


1. Metalloproteinase. Wikipedi a [online]. 29 th Febru ary 2008. Available from: http:/ / en.wikipedi wiki/ Metalloproteinase.

2. Nagase H, Woessner JF jr. Matrix metalloproteinases. J Bi ol Chem 1999; 274(31): 21491– 21494.

3. Rena ud S, Leppert D. Matrix metalloproteinases in ne uromuscular dise ase. Muscle Nerve 2007; 36(1): 1– 13.

4. Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expressi on incre ases after cerebral focal ischemi a in rats: inhibiti on of matrix metalloproteinase- 9 reduces infarct size. Stroke 1998; 29(5):1020– 1030.

5. Wang J, Tsirka SE. Contributi on of extracellular proteolysis and microgli a to intracerebral hemorrhage. Ne urocrit Care 2005; 3(1): 77– 85.

6. Mastro i anni CM, Li uzzi GM. Matrix metalloproteinase dysregulati on in HIV infecti on: implicati ons for therape utic strategi es. Trends Mol Med 2007; 13(11): 449– 459.

7. Valenzuela MA, Collados L, Kettlun AM, González F, Carti er L. Incre ased activity of metalloproteinases and their inhibitors in cerebrospinal fluid of pati ents with tropical spastic paraparesis. Rev Med Chil 2000; 128(6): 585– 592.

8. Larsen PH, DaSilva AG, Conant K, Yong VW. Myelin formati on during development of the CNS is delayed in matrix metalloproteinase- 9 and - 12 null mice. J Ne urosci 2006; 26(8): 2207– 2214.

9. Yong VW, Power C, Forsyth P, Edwards DR. Metalloproteinases in bi ology and pathology of the nervo us system. Nat Rev Ne urosci 2001; 2(7): 502– 511.

10. Meighan SE, Meighan PC, Cho udhury P,Davis CJ, Olson ML, Zornes PA et al. Effects of extracellular matrix- degrading prote ases matrix metalloproteinases 3 and 9 on spati al le arning and synaptic plasticity. J Ne urochem 2006; 96(5): 1227– 1241.

11. Rosenberg GA. Matrix metalloprotei­nases and ne uro inflammati on in multiple sclerosis. Ne urosci entist 2002; 8(6): 586– 595.

12. Thornton P, Pinte a ux E, Allan SM, Roth­well NJ. Matrix metalloproteinase- 9 and urokinase plasminogen activator medi ate interle ukin‑1‑induced ne urotoxicity. Mol Cell Ne urosci 2008; 37(1): 135– 142.

13. Anthony DC, Hughes P, Perry VH. The evidence for primary axonal loss in multiple sclerosis. Rev Ne urol 2000; 30(12): 1203– 1208.

14. Pagenstecher A, Stalder AK, Kincaid CL, Shapiro SD, Campbell IL. Differenti al expressi on of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mo use central nervo us system in normal and inflammatory states. Am J Pathol 1998; 152(3): 729– 741.

15. Ki esei er BC, Ki efer R, Clements JM, Miller K, Wells GM, Schweitzer T et al. Matrix metalloproteinase- 9 and - 7 are regulated in experimental a uto immune encephalomyelitis. Brain 1998; 121(Pt 1): 159– 166.

16. Nygårdas PT, Hinkkanen AE. Up-re­gulati on of MMP‑ 8 and MMP‑ 9 activity in the BALB/ c mo use spinal cord correlates with the severity of experimental a uto immune encephalomyelitis. Clin Exp Immunol 2002; 128(2): 245– 254.

17. Jovanova- Nesic K, Shoenfeld Y. MMP‑ 2, VCAM‑1 and NCAM- 1 expressi on in the brain of rats with experimental a uto immune encephalomyelitis as a trig­ger mechanism for synaptic plasticity and pathology. J Ne uro immunol 2006; 181(1– 2): 112– 121.

18. Wells GM, Catlin G, Cossins JA, Mangan M, Ward GA, Miller KM et al. Qu antitati on of matrix metalloproteinases in cultured rat astrocytes using the polymerase chain re acti on with a multi‑competitor cDNA standard. Gli a 1996; 18(4): 332– 340.

19. Hewson AK, Smith T, Leonard JP, Cuz­ner ML. Suppressi on of experimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor Ro31– 9790. Inflamm Res 1995; 44(8): 345– 349.

20. Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage- medi ated proteolysis and matrix invasi on in mice. Proc Natl Acad Sci U S A 1996; 93(9): 3942– 3946.

21. We aver A, Goncalves da Silva A, Nuttall RK, Edwards DR, Shapiro SD, Rivest S et al. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/ Th2 polarizati on. FASEB J 2005; 19(12): 1668– 1670.

22. Esparza J, Kruse M, Lee J, Micha ud M,Madri JA. MMP‑ 2 null mice exhibit an e arly onset and severe experimental a uto immune encephalomyelitis due to an incre ase in MMP‑ 9 expressi on and activity. FASEB J 2004; 18(14): 1682– 1691.

23. Dubi os B, Masure S, Hurtenbach U, Paemen L, Heremans H, van den Oord J et al. Resistance of yo ung gelatinase B- defici ent mice to experimental a uto immune encephalomyelitis and necrotizing tail lesi ons. J Clin Invest 1999; 104(11): 1507– 1515.

24. Fainardi E, Castellazzi M, Bellini T, Man­frinato MC, Baldi E, Casetta I et al. Cerebrospinal fluid and serum levels and intrathecal producti on of active matrix metalloproteinase- 9 (MMP‑ 9) as markers of dise ase activity in pati ents with multiple sclerosis. Mult Scler 2006; 12(3): 294– 301.

25. Wa ubant E, Go odkin DE, Gee L, Bacchetti P, Slo an R, Stewart T et al. Serum MMP‑ 9 and TIMP‑ 1 levels are related to MRI activity in relapsing multiple sclerosis. Ne urology 1999; 53(7): 1397– 1401.

26. Lee MA, Palace J, Stabler G, Ford J, Ge aring A, Miller K. Serum gelatinase B, TIMP‑ 1 and TIMP‑ 2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain 1999; 122(Pt 2): 191– 197.

27. Kolb SA, Lahrtz F, Pa ul R, Leppert D, Nadal D, Pfister HW et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulati on of MMP‑ 9 and TIMP‑ 1 in cerebrospinal fluid. J Ne uro immunol 1998; 84(2): 143– 150.

28. Lindberg RL, De Gro ot CJ, Montagne L, Freitag P, van der Valk P, Kappos L et al. The expressi on profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesi ons and normal appe aring white matter of multiple sclerosis. Brain 2001; 124(Pt 9): 1743– 1753.

29. Vos CM, van Haastert ES, de Gro ot CJ, van der Valk P, de Vri es HE. Matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesi ons. J Ne uro immunol 2003; 138(1– 2): 106– 114.

30. Maeda A, Sobel RA. Matrix metalloproteinases in the normal human central nervo us system, microgli al nodules, and multiple sclerosis lesi ons. J Ne uropathol Exp Ne urol 1996; 55(3): 300– 309.

31. Werring DJ, Brassat D, Dro ogan AG, Clark CA, Symms MR, Barker GJ et al. The pathogenesis of lesi ons and normal- appe aring white matter changes in multiple sclerosis: a seri al diffusi on MRI study. Brain 2000; 123(Pt 8): 1667– 1676.

32. Corre ale J, Bassani Molinas Mde L. Temporal vari ati ons of adhesi on molecules and matrix metalloproteinases in the co urse of MS. J Ne uro immunol 2003; 140(1– 2): 198– 209.

33. Sastre‑Garriga J, Comabella M, Bri eva L,Rovira A, Tintoré M, Montalban X. Decre ased MMP‑ 9 producti on in primary progressive multiple sclerosis pati ents. Mult Scler 2004; 10(4): 376– 380.

34. Rosenberg GA, Kornfeld M, Estrada E,Kelley RO, Li otta LA, Stetler-Stevenson WG. TIMP‑ 2 reduces proteolytic opening of blo od- brain barri er by type IV collagenase. Brain Res 1992; 576(2): 203– 207.

35. Abraham M, Shapiro S, Karni A, Weiner HL, Miller A. Gelatinases (MMP‑ 2 and MMP‑ 9) are preferenti ally expressed by Th1 vs. Th2 cells. J Ne uro immunol 2005; 163(1– 2): 157– 164.

36. Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan- 1 regulates chemokine mobilizati on and transepitheli al efflux of ne utrophils in acute lung injury. Cell 2002; 111(5): 635– 646.

37. Mohan MJ, Se aton T, Mitchell J, Howe A,Blackburn K, Burkhart W et al. The tumor necrosis factor‑alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Bi ochemistry 2002; 41(30): 9462– 9469.

38. Van Den Steen PE, Wuyts A, Husson SJ, Pro ost P, Van Damme J, Opdenakker G.Gelatinase B/ MMP‑ 9 and ne utrophil collagenase/ MMP‑ 8 process the chemokines human GCP- 2/ CXCL6, ENA‑78/ CXCL5 and mo use GCP- 2/ LIX and modulate their physi ological activiti es. Eur J Bi ochem 2003; 270(18): 3739– 3749.

39. Chandler S, Co ates R, Ge aring A, Lury J,Wells G, Bone E. Matrix metalloproteinases degrade myelin basic protein. Ne urosci Lett 1995; 201(3): 223– 226.

40. Anthony DC, Miller KM, Fe arn S, Town­send MJ, Opdenakker G, Wells GM et al. Matrix metalloproteinase expressi on in an experimentally‑induced DTH model of multiple sclerosis in the rat CNS. J Ne uro immunol 1998; 87(1– 2): 62– 72.

41. Newman TA, Wo olley ST, Hughes PM, Sibson NR, Anthony DC, Perry VH. T- cell-  and macrophage- medi ated axon damage in the absence of a CNS- specific immune response: involvement of metalloproteinases. Brain 2001; 124(Pt 11): 2203– 2214.

42. Gu Z, Cui J, Brown S, Fridman R, Mo­bashery S, Strongin AY et al. A highly specific inhibitor of matrix metalloproteinase- 9 rescues laminin from proteolysis and ne urons from apoptosis in transi ent focal cerebral ischemi a. J Ne urosci 2005; 25(27): 6401– 6408.

43. Mari ani SM, Matiba B, Bäumler C, Krammer PH. Regulati on of cell surface APO- 1/ Fas (CD95) ligand expressi on by metalloprote ases. Eur J Immunol 1995; 25(8): 2303– 2307.

44. Gu Z, Ka ul M, Yan B, Kridel SJ, Cui J, Strongin A et al. S- nitrosylati on of matrix metalloproteinases: signaling pathway to ne uronal cell de ath. Sci ence 2002; 297(5584): 1186– 1190.

45. Leppert D, Wa ubant E, Bürk MR, Ok­senberg JR, Ha user SL. Interferon beta‑1b inhibits gelatinase secreti on and in vitro migrati on of human T cells: a possible mechanism for tre atment efficacy in multiple sclerosis. Ann Ne urol 1996; 40(6): 846– 852.

46. Boz C, Ozmenoglu M, Veli oglu S, Kilinc K, Orem A, Ali oglu Z et al. Matrix metalloproteinase- 9 (MMP‑ 9) and tissue inhibitor of matrix metalloproteinase (TIMP‑ 1) in pati ents with relapsing- remitting multiple sclerosis tre ated with interferon beta. Clin Ne urol Ne urosurg 2006; 108(2): 124– 128.

47. Wa ubant E, Go odkin D, Bostrom A,Bacchetti P, Hi etpas J, Lindberg R et al. IFNbeta lowers MMP‑ 9/ TIMP‑ 1 rati o, which predicts new enhancing lesi ons in pati ents with SPMS. Ne urology 2003; 60(1): 52– 57.

48. Rosenberg GA, Dencoff JE, Corre a N Jr, Reiners M, Ford CC. Effect of stero ids on CSF matrix metalloproteinases in multiple sclerosis: relati on to blo od- brain barri er injury. Ne urology 1996; 46(6): 1626– 1632.

49. Sellebjerg F, Christi ansen M, Jensen J, Frederiksen JL. Immunological effects oforal high‑dose methylprednisolone in acute optic ne uritis and multiple sclerosis. Eur J Ne urol 2000; 7(3): 281– 289.

50. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93(3): 178– 193.

51. Wojtowicz- Praga S, Torri J, Johnson M,Steen V, Marshall J, Ness E et al. Phase I tri al of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to pati ents with advanced lung cancer. J Clin Oncol 1998; 16(6): 2150– 2156.

52. Noble LJ, Donovan F, Igarashi T, Go u­ssev S, Werb Z. Matrix metalloproteinases limit functi onal recovery after spinal cord injury by modulati on of e arly vascular events. J Ne urosci 2002; 22(17): 7526– 7535.

53. Hsu JY, McKeon R, Go ussev S, Werb Z, Lee JU, Trivedi A et al. Matrix metalloproteinase- 2 facilitates wo und he aling events that promote functi onal recovery after spinal cord injury. J Ne urosci 2006; 26(39): 9841– 9850.

54. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting le ukocyte MMPs and transmigrati on: minocycline as a potenti al therapy for multiple sclerosis. Brain 2002; 125(Pt 6): 1297– 1308.

55. Metz LM, Zhang Y, Ye ung M, Patry DG, Bell RB, Sto i an CA et al. Minocycline reduces gadolini um- enhancing magnetic resonance imaging lesi ons in multiple sclerosis. Ann Ne urol 2004; 55(5): 756.

56. Nelissen I, Martens E, Van den Steen PE, Pro ost P, Ronsse I, Opdenakker G. Gelatinase B/ matrix metalloproteinase- 9 cle aves interferon‑beta and is a target for immunotherapy. Brain 2003; 126(Pt 6): 1371– 1381.

57. Kanesaka T, Mori M, Hattori T, OkiT, Ku­wabara S. Serum matrix metallo­proteinase- 3 levels correlate with disease activity in relapsing- remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2006; 77(2): 185– 188.

58. Acris Antibodi es GmbH [online]. Avai-lable from: http:/ / www.acris- an­ti­bodi focus_revi ew/ focusrevi ew0001- MMP.php.

59. Emdbi osci [online]. Available from: http:/ / www.emdbi osci html/ CBC/ matrix_metalloproteinase_MMP.htm.

Paediatric neurology Neurosurgery Neurology
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account