MS and MMP-I

(Matrix-Metalloproteinase Inhibitors)

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The enclosed test reflects a medline search on matrix metalloproteinase OR gelatinase AND multiple sclerosis performed on 20.9.99 . Only 34 hits were found, all since 1994, and they were supplemented with abstracts from the MS congress in Basel, September 1999. Finally, I have rearranged the text (generally quotations from various abstracts) according to relevant topics. It is, however, not constructed in accordance with the other links of this homepage and the quotations may be difficult to read in a comprehensive way.

Abbreviations used in this page:

The "MMP-Family":

At least 14 structurally related [19], zinc (and calcium) dependent endopeptidases, that are collectively responsive for the metabolism of extracellular matrix proteins with a physiological function in, e.g. wound healing and angiosynthesis. Excess syntheses and production of these proteins lead to the accelerated matrix degradation [7]. The four classes of MMPs: collagenases, stromelysins, membrane-type metalloproteinases and gelatinases [3]. In contrast (?), gelatinases are also described as Type-IV collagenases [25]. Described here as pathological in MS:

Pathology, general, experimental:

Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS [16]. The demyelination process is, in part, due to an inflammatory response in which CD4+ and CD8+ T cells and macrophages infiltrate white matter. These T cells have the capacity to secrete various proinflammatory chemokines [17]. The production of MMP-2 and MMP-9 is increased in nerve tissue in chronic inflammatory demyelinating polyneuropathy but. Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity [2]. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques [5]. [define a role of alpha4 integrin in the disease process in mediating the induction and coordinate activation of] MMP-2, which facilitates T-cell transmigration [6]. MMP-7, MMP-8, and MMP-9 provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin [9]. ... the expression of at least seven MMPs. Of these, MMP-7 showed the most significant change, being elevated over 500 fold with onset of clinical symptoms and peaking at maximum disease severity. Of the other six MMPs detected, MMP-9 showed a modest 5 fold increase which peaked at the onset of clinical signs and then declined during the most severe phase of the disease [18]. MMP-7 was localised to the invading macrophages within the inflammatory lesions [18]. MMP activity is increased over three-fold in neonatal rat astrocyte cultures following stimulation with lipopolysaccharide (LPS) [21]. In animal studies, intracerebral injection of MMP-2 opens the BBB by disrupting the basal lamina around capillaries [25]. ...suggest that increased MMP-9 is associated with an open BBB [25]. Upregulation of MMPs is a key feature in MS where the phenomenon may contribute to BBB disruption, myelin degradation and epitope spreading due to encephalitogenic myelin fragments [31]. ... suggests that MMP-9 is upregulated in the invading cells themselves [33]. The similar increase of MMP-2 and MMP-9 in both demyelinating and nondemyelinating neuropathies raises doubts about whether MMPs play a primary role in demyelination [2].

Pathology, TNF-alpha:

Release of the pro-inflammatory cytokine, TNF-A, from its membrane-bound precursor is an MMP-dependent process [19]. Conversely, TNF-A-converting enzyme and FasL-converting enzyme, can be blocked by MMPIs [10]. TNF-A is a potent cytokine, secreted primarily by activated monocytes and macrophages, that possesses a broad range of immunomodulating properties [20]. The enzyme that processes precursor TNF-A has previously been identified as a microsomal metalloprotease called TNF-A converting enzyme (TACE) [20]. MMPs] contribute to connective tissue breakdown and the release of the pro-inflammatory cytokine TNF-A [21]. The release of mature TNF-A from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-A into the circulation of endotoxin challenged rats [28].

Pathology, MMPs and fibrinolytics:

The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including MS, is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs) [3]. The expression of t-PA and a number of MMPs as well as PAI-1 and TIMP-1 was analyzed in the CNS of normal control and MS cases. In general, PAI-1 expression paralleled that of t-PA. These observations ... pinpoint t-PA, a rate-limiting enzyme, and MMP-9 as therapeutic targets in MS [24]. The proteolytic activities of MMPs and plasminogen activators as well as their inhibitors are important in maintaining the integrity of the extracellular matrix [29]. The activation of u-PA & t-PA is the key initiator of the activation cascade of the four classes of MMPs: collagenases, stromelysins, membrane-type metalloproteinases and gelatinases [3].

MS (= human) and MMP:

The sustained increase of MMP-9 in clinically stable multiple sclerosis supports the concept that multiple sclerosis is associated with ongoing proteolysis that may result in progressive tissue damage [5]. Our findings indicate that MMP-9 and MMP-7 may contribute to the pathogenesis of inflammatory diseases of the CNS [11]. Similar finding in EAN and Guiallain-Barre syndrome [12]. MMP-7 immunoreactivity was very strong in parenchymal macrophages in active demyelinating MS lesions. but not in normal controls or in extracranial macrophages of MS-patients [13]. MMP-9 immunoreactivity was found in many blood vessels of active demyelinating MS lesions [13].
MMP-2, -7 & -9 expression was found to be up-regulated in microglia/macrophages within acute MS lesions. In active-chronic MS lesions, MMP-2 & -7 expression was pronounced in the active borders. In chronic MS lesions, the expression of matrilysin was confined to macrophages within perivascular cuffs, supporting a role for these enzymes as mediators of blood-brain barrier breakdown and tissue destruction [15]. MMP-2 & -9 were detected predominantly in astrocytes and microglia throughout normal control white matter. In demyelinating lesion there is widespread prominent expression of MMP-9 in reactive astrocytes and macrophages. TIMP-1 was also present in the vessel matrix and in lesional macrophages [24]. An increase of Se-MMP-9 levels predict disease activity in RR-MS [32]. High MMP-9 and low TIMP-1 serum levels are detected in RR-MS patients the month before gadolinium-enhanced lesions appears [37]. In comparison to controls (n=9), patients with RR-MS (n=9) showed a 3-fold increase in the MMP-2/TIMP-1 ratio and a 2.2 fold MMP-7/TIMP-1 ratio. Patients with SP-MS (n=9) showed similarly an elevation of 3 and 3.5 fold [36]

Potential Treatment:

Direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention [1]. The selective inhibition of MMP-9 could be a useful approach [5]. We have shown that BB-1101, a broad spectrum hydroxamic acid-based combined inhibitor of MMP activity and TNF processing, reduces the clinical signs of EAE [18]. A hydroxamate inhibitor of MMPs, Ro31-9790 (50 mg/kg) significantly reduced the clinical severity of adoptively transferred EAE [26]. A hydroxamate matrix metalloprotease inhibitor, GM 6001m suppressed the development or reversed clinical EAE in a dose-dependent way. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease [27]. Synthetic hydroxamic acid-based metalloproteinase inhibitors also mentioned under TNF-A [28]. Current syntethic MMP-inhibitors are not specific and would cause side-effects due to undesired broad-spectrum inhibition of MMPs [31]. The ... proteinase t-PA and MMP-9 ... are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in-vitro experiments to inhibit MMP-9 [38].

Interferon-beta and MMPs:

IFB can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases [8]. The clinical benefits of IFN beta-1b treatment in multiple sclerosis patients may in part be a result of this drug's ability to decrease the migration of PBMNCs in spite of a chemotactic gradient through an effect on MMP-9 [14]. In human T cells, interleukin-2 induces gelatinase secretion and enhances gelatinase-dependent migration across an artificial basement membrane-like layer in vitro; pretreatment of T cells with interferon beta-1b for 48 hours decreased dose dependently interleukin-2-induced gelatinase production and secretion. In parallel to the downregulation of gelatinase secretion, pretreatment with IFB-1b inhibited T-cell migration across the basement membrane in vitro by up to 90% [22]. IFB-1b downregulates the interleukin-2 receptor alpha-chain and lowered the affinity of interleukin-2 to the cell surface by 30%, which may represent an additional mechanism for the observed effects of IFB-1b [22]. The dramatic effects of IFB-1b on gelatinase expression and migration raise the possibility that its beneficial effects in multiple sclerosis may result from interference with the capacity of activated T cells to traverse the basement membrane and migrate to the central nervous system [22]. IFB-1b decreases the in vitro migration of activated T lymphocytes predominantly due to the activity of MMP-9, whose levels were decreased by IFB-1b [23]. The efficacy of IFB may result (among other factors) from its suppressive activity on MMP-9 secretion in T-cells [31]. Suppression of Se-MMP-9 indicates that IFB-1b is [also] active in PP-MS; in contrast, MMP-2 levels were not affected. [32]. IFB-1a may decrease the expression of MMP-9 & MMP-3 by the glial cells. [34]. Increased serum TIMP-1 levels may partially explain the effect of IFB-1a (Avonex) in RR-MS [37]. These in vitro data do not confirm a significant role of IFB in the control of MMP-9 and TIMP-1 release, probably due to persistant monocyte dysfunction in MS. [35].

Glucocorticoids and MMPs:

Steroids may improve capillary function by reducing activity of MMP-9 and uPA and increasing levels of TIMPs [25].

Tetracyclines and MMPs:

When 23 tetracycline analogues were compared, significant differences in MMP-9 inhibition were found between various compounds. 4-epioxytetracycline base, 4-epichlortetracycline, meclocyclinesulfosalicylate, and unmodified metacycline and minocycline proved to be the most potent MMP-9 inhibitors. This activity of tetracyclines was clearly dissociated from their antimicrobial activity [30].

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  1. Skotnicki JS. Zask A. Nelson FC. Albright JD. Levin JI.Design and synthetic considerations of matrix metalloproteinase inhibitors. Annals of the New York Academy of Sciences. 878:61-72, 1999 Jun 30.
  2. Leppert D. Hughes P. Huber S. Erne B. Grygar C. Said G. Miller KM. Steck AJ. Probst A. Fuhr P. Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy. Neurology. 53(1):62-70, 1999 Jul 13.
  3. Cuzner ML. Opdenakker G. Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. [Review] [111 refs]. J Neuroimmunology. 94(1-2):1-14, 1999.
  4. Opdenakker G. Metalloproteinases and specific inhibitors in multiple sclerosis: from blood to brain or vice versa? [editorial; comment]. Comment on: Brain 1999;122:191-7. Brain. 1999;122:181-2.
  5. Leppert D. Ford J. Stabler G. Grygar C. Lienert C. Huber S. Miller KM. Hauser SL. Kappos L. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121:2327-34, 1998
  6. Graesser D. Mahooti S. Haas T. Davis S. Clark RB. Madri JA. The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis. Laboratory Investigation. 78(11):1445-58, 1998 Nov.
  7. Borkakoti N. Matrix metalloproteases: variations on a theme. [Review] [76 refs]. Progress in Biophysics & Molecular Biology. 70(1):73-94, 1998.
  8. Yong VW. Chabot S. Stuve O. Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. [Review] [80 refs]. Neurology. 51(3):682-9, 1998 Sep.
  9. Anthony DC. Miller KM. Fearn S. Townsend MJ. Opdenakker G. Wells GM. Clements JM. Chandler S. Gearing AJ. Perry VH. Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS. Journal of Neuroimmunology. 87(1-2):62-72, 1998.
  10. Liedtke W. Cannella B. Mazzaccaro RJ. Clements JM. Miller KM. Wucherpfennig KW. Gearing AJ. Raine CS. Effec-tive treatment of models of multiple sclerosis by matrix metal-loproteinase inhibitors. Annals of Neurology. 44:35-46, 1998.
  11. Kieseier BC. Kiefer R. Clements JM. Miller K. Wells GM. Schweitzer T. Gearing AJ. Hartung HP. Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. Brain. 121:159-66, 1998.
  12. Kieseier BC. Clements JM. Pischel HB. Wells GM. Miller K. Gearing AJ. Hartung HP. Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barre syndrome. Annals of Neurology. 43(4):427-34, 1998 Apr.
  13. Cossins JA. Clements JM. Ford J. Miller KM. Pigott R. Vos W. Van der Valk P. De Groot CJ. Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions. Acta Neuropathologica. 94(6):590-8, 1997 Dec.
  14. Stuve O. Chabot S. Jung SS. Williams G. Yong VW. Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9. Journal of Neuroimmunology. 80(1-2):38-46, 1997 Dec.
  15. Anthony DC. Ferguson B. Matyzak MK. Miller KM. Esiri MM. Perry VH. Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathology & Applied Neurobiology. 23(5):406-15, 1997.
  16. Benveniste EN. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. [Review] [107 refs]. J. Molecular Medicine. 75:165-73, 1997.
  17. Biddison WE. Taub DD. Cruikshank WW. Center DM. Connor EW. Honma K. Chemokine and matrix metalloproteinase secretion by myelin proteolipid protein-specific CD8+ T cells: potential roles in inflammation. Journal of Immunology. 158(7):3046-53, 1997 Apr 1.
  18. Clements JM. Cossins JA. Wells GM. Corkill DJ. Helfrich K. Wood LM. Pigott R. Stabler G. Ward GA. Gearing AJ. Miller KM. Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-alpha inhibitor. Journal of Neuroimmunology. 74:85-94, 1997.
  19. Chandler S. Miller KM. Clements JM. Lury J. Corkill D. Anthony DC. Adams SE. Gearing AJ. Matrix metalloproteina-ses, tumor necrosis factor and multiple sclerosis: an overview. [Review] [95 refs]. J. Neuroimmunology. 72:155-61, 1997.
  20. Moss ML. Jin SL. Becherer JD. Bickett DM. Burkhart W. Chen WJ. Hassler D. Leesnitzer MT. McGeehan G. Milla M. Moyer M. Rocque W. Seaton T. Schoenen F. Warner J. Willard D. Structural features and biochemical properties of TNF-alpha converting enzyme (TACE). [Review] [18 refs]. Journal of Neuroimmunology. 72(2):127-9, 1997 Feb.
  21. Wells GM. Catlin G. Cossins JA. Mangan M. Ward GA. Miller KM. Clements JM. Quantitation of matrix metalloproteinases in cultured rat astrocytes using the polymerase chain reaction with a multi-competitor cDNA standard. GLIA. 18(4):332-40, 1996 Dec.
  22. Leppert D. Waubant E. Burk MR. Oksenberg JR. Hauser SL. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treat-ment efficacy in multiple sclerosis. Ann. Neurology 40(6):846-52, 1996 Dec.
  23. Stuve O. Dooley NP. Uhm JH. Antel JP. Francis GS. Williams G. Yong VW. Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Annals of Neurology. 40(6):853-63, 1996.
  24. Cuzner ML. Gveric D. Strand C. Loughlin AJ. Paemen L. Opdenakker G. Newcombe J. The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. J. Neuropa-thology & Experimental Neurology. 55:1194-204, 1996
  25. Rosenberg GA. Dencoff JE. Correa N Jr. Reiners M. Ford CC. Effect of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology. 46(6):1626-32, 1996 Jun.
  26. Hewson AK. Smith T. Leonard JP. Cuzner ML. Suppression of experimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor Ro31-9790. Inflammation Research. 44(8):345-9, 1995 Aug.
  27. Gijbels K. Galardy RE. Steinman L. Reversal of experim-ental autoimmune encephalomyelitis with a hydroxamate inhi-bitor of matrix metalloproteases.J Clin Invest 1994;94:2177-82
  28. Gearing AJ. Beckett P. Christodoulou M. Churchill M. Clements J. Davidson AH. Drummond AH. Galloway WA. Gilbert R. Gordon JL. et al. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 370(6490):555-7, 1994 Aug 18.
  29. Romanic AM. Madri JA. Extracellular matrix-degrading proteinases in the nervous system. [Review] [117 refs], Brain Pathology. 4(2):145-56, 1994 Apr
  30. Paemen L. Martens E. Norga K. Masure S. Roets E. Hoogmartens J. Opdenakker G. The gelatinase inhibitory activity of tetracyclines and chemically modified tetracycline analogues as measured by a novel microtiter assay for inhibitors. Biochemical Pharmacology. 52(1):105-11, 1996
  31. Leppert D, Lindberg R, Kappos L. Matrix metalloproteinase inhibitors: current and novel drugs for MS therapy. Multiple Sclerosis 1999;5(Suppl. 1):S17.
  32. Yushchenko M, Mäder M, Bitsch A, Kitze B, Bogumil T, Dressel A, Kolb A, Elitok E, Bahner D, Poser S, Weber F. Treatment with interferonb-1b (IFN-beta-1b) suppressed serum levels of matriix metalloproteainase-9 (MMP-9) in patients with primary progressive multiple sclerosis (PPMS). Multiple Sclerosis 1999;5(Suppl. 1):S18.
  33. Heidenreich F, Seifert T, Kracke A, Markmann S, Wurster U, Lichtinghagen R. Matrix metalloproteinnase-9 and its inhibitors TIMP-1 and TIMP-2 in mononuclear blood cells of MS patients at the mRNA and protein level. Multiple Sclerosis 1999;5(Suppl. 1):S105.
  34. Gignoux L, Chalon A, Giraudon P, Belin MF, Confavreux C. Cytokine balance, metalloproteinases and glial cells: IFNb 1a decreases in vitro the capacity for TNF a to induce MMP-9 and MMP-3 expression in human astrocytes. Multiple Sclerosis 1999;5(Suppl. 1):S105.
  35. Mazzarino C, Reggio E, Malaponte G, La Rosa I, Porto A, Zammataro N, Petralia S, L'Episcopo R, Patti F, Reggio A. Cytokine modulation in vitro of monocyte release of MMP-9 and TIMP-1 in multiple sclerosis patients: preliminary research. Multiple Sclerosis 1999;5(Suppl. 1):S106.
  36. Galboiz Y, Shapiro S, Labat N, Honigman S, Rawashdeh H, Kinarty A, Miller A. Distinct profiles of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in various clinical multiple sclerosis subtypes. Multiple Sclerosis 1999;5(Suppl. 1):S106.
  37. Waubant E, Gee L, Bacchetti P, Miller K, Stabler G, Goodkin D. Interferon beta-1a may increase tissue inhibitor of matrix metalloproteinase-type 1 (TIMP-1) serum levels in relapsing remitting multiple sclerosis (RRMS). Multiple Sclerosis 1999;5(Suppl. 1):S106.
  38. Dubois B, D'Hooghe MB, De Lepeleire K, Ketelaer P, Opdenakker G, Carton H. Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis. Multiple Sclerosis 1998;4:74-8.
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Revised Nov 21, 2000