MS and MMP-I
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
Abbreviations used in this page:
MMPs: matrix metalloproteinases
MMPIs: matrix metalloproteinase inhibitors
TIMP-1/-2: endogenous inhibitors
IFB: Interferon beta
EAE: Autoimmune experimental encephalitis
EAN: autoimmune experimental neuritis
GBS: Guillain-Barre syndrome
TNF-A: Tumor necrosis faxtor alpha
TACE: TNF-alpha converting enzyme
t-PA: tissue-type plasminogen activator
PAI-1: plasminogen activator inhibitor-1
PBMNC: peripheral blood mononuclear cells
RR-MS: recurrant-remittant multiple sclerosis
PP-MS: primary progressive MS
SP-MS: secondary progressive MS
At least 14 structurally related , 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 . The four classes
of MMPs: collagenases, stromelysins, membrane-type metalloproteinases and
gelatinases . In contrast (?), gelatinases are also described as Type-IV
collagenases . Described here as pathological in MS:
Pathology, general, experimental:
MMP-2: Gelatinase A (72-kd gelatinase)
MMP-3: Stromelysin (as MMP 10, 55kd)
MMP-7: Matrilysin (28 kd)
MMP-8: Collagenase (as MMP 1 & 13, 55kd)
MMP-9: Gelatinase B (92-kd gelatinase)
(MMP-14,-15,-16): Membrane type MMPs (66kd)
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 . 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 . 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 .
Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis
plaques . [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 . MMP-7, MMP-8, and MMP-9 provoked recruitment
of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss
of myelin . ... 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 . MMP-7 was localised to the invading macrophages within
the inflammatory lesions . MMP activity is increased over three-fold
in neonatal rat astrocyte cultures following stimulation with lipopolysaccharide
(LPS) . In animal studies, intracerebral injection of MMP-2 opens the
BBB by disrupting the basal lamina around capillaries . ...suggest
that increased MMP-9 is associated with an open BBB . 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 . ... suggests that MMP-9 is upregulated in the invading
cells themselves . 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 .
Release of the pro-inflammatory cytokine, TNF-A, from
its membrane-bound precursor is an MMP-dependent process . Conversely,
TNF-A-converting enzyme and FasL-converting enzyme, can be blocked by MMPIs
. TNF-A is a potent cytokine, secreted primarily by activated monocytes
and macrophages, that possesses a broad range of immunomodulating properties
. The enzyme that processes precursor TNF-A has previously been identified
as a microsomal metalloprotease called TNF-A converting enzyme (TACE) .
MMPs] contribute to connective tissue breakdown and the release of the
pro-inflammatory cytokine TNF-A . 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 .
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)
. 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 . The
proteolytic activities of MMPs and plasminogen activators as well as their
inhibitors are important in maintaining the integrity of the extracellular
matrix . 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 .
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 . Our
findings indicate that MMP-9 and MMP-7 may contribute to the pathogenesis
of inflammatory diseases of the CNS . Similar finding in EAN and Guiallain-Barre
syndrome . 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 . MMP-9 immunoreactivity was found in many
blood vessels of active demyelinating MS lesions .
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 . 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 . An
increase of Se-MMP-9 levels predict disease activity in RR-MS . High
MMP-9 and low TIMP-1 serum levels are detected in RR-MS patients the month
before gadolinium-enhanced lesions appears . 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 
Direct inhibition of enzyme action provides a particularly
attractive target for therapeutic intervention . The selective inhibition
of MMP-9 could be a useful approach . 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 . A hydroxamate
inhibitor of MMPs, Ro31-9790 (50 mg/kg) significantly reduced the clinical
severity of adoptively transferred EAE . 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 . Synthetic hydroxamic acid-based metalloproteinase
inhibitors also mentioned under TNF-A . Current syntethic MMP-inhibitors
are not specific and would cause side-effects due to undesired broad-spectrum
inhibition of MMPs . 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 .
Interferon-beta and MMPs:
IFB can reduce T-cell migration by inhibiting the activity
of T-cell matrix metalloproteinases . 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 . 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% . 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
. 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
. 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 . The efficacy of IFB may result (among other factors) from
its suppressive activity on MMP-9 secretion in T-cells . Suppression
of Se-MMP-9 indicates that IFB-1b is [also] active in PP-MS; in contrast,
MMP-2 levels were not affected. . IFB-1a may decrease the expression
of MMP-9 & MMP-3 by the glial cells. . Increased serum TIMP-1 levels
may partially explain the effect of IFB-1a (Avonex) in RR-MS . 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. .
Glucocorticoids and MMPs:
Steroids may improve capillary function by reducing activity
of MMP-9 and uPA and increasing levels of TIMPs .
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
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considerations of matrix metalloproteinase inhibitors. Annals of the New
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A, Elitok E, Bahner D, Poser S, Weber F. Treatment with interferonb-1b
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Heidenreich F, Seifert T, Kracke A, Markmann S, Wurster U, Lichtinghagen
R. Matrix metalloproteinnase-9 and its inhibitors TIMP-1 and TIMP-2 in
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Mazzarino C, Reggio E, Malaponte G, La Rosa I, Porto A, Zammataro N, Petralia
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and metacycline in secondary progressive multiple sclerosis. Multiple Sclerosis
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Revised Nov 21, 2000