IFN-ß Lowers MMP-9/TIMP-1 Ratio, Which Predicts New Enhancing Lesions In SPMS
Waubant E, Goodkin D, Bostrom A, Bacchetti P, Hietpas J, Lindberg R, Leppert D
Neurology 2003 Jan 14;60(1):52-7
UCSF Multiple Sclerosis Center and; University of California, Department of Epidemiology and BioStatistics, San Francisco, CA
PMID# 12525717; UI# 22413813
- Determine Serum levels of Matrix MetalloProteinase-2 (MMP-2), MMP-9, Tissue Inhibitor of MetalloProteinase-1 (TIMP-1), and TIMP-2 in patients with Secondary/Progressive (SP) MS
- Determine the relationship between Serum levels and MRI activity
- Evaluate the effect of Interferon (IFN-ß) therapy on these measures
High Serum levels of MMP-9 and low levels of TIMP-1 predict the appearance of new Gadolinium-enhancing (Gd+) lesions in Relapsing/Remitting (RR) MS.
Monthly Gd+ Brain MRI and measures of serum MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals were performed for up to 3 years in 33 patients with SPMS participating in a Phase III study of IFN-ß-1b.
Patients who developed new Gd+ lesions had higher levels of MMP-9 than patients who did not develop Gd+ lesions (median 351 vs 226 ng/mL, p = 0.049).
The ratio of MMP-9/TIMP-1 predicted new Gd+ lesion on the concurrent scan (OR = 2.23, 95% CI 0.99 to 4.99, p = 0.052) and on the following scan (OR = 2.16, 95% CI 1.01 to 4.63, p = 0.048), whereas levels of MMP-2/TIMP-2 did not.
Median levels of TIMP-1 were higher and MMP-9 trended lower for IFN-ß compared to placebo recipients (TIMP-1: 1,450 vs 1,185 ng/mL, p = 0.024; MMP-9: 225 vs 339 ng/mL, p = 0.081). IFN-ß did not influence levels of MMP-2 and TIMP-2.
The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFN-ß-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
Intrathecal Synthesis Of Matrix MetalloProteinase-9 In Multiple Sclerosis: Implication For Pathogenesis
Liuzzi GM, Trojano M, Fanelli M, Avolio C, Fasano A, Livrea P, Riccio P
Mult Scler 2002 May;8(3):222-8
University of Bari, Department of Biochemistry and Molecular Biology, Italy
Matrix MetalloProteinase-9 (MMP-9) was detected by Zymography and Enzyme-Linked Immunosorbent Assay (ELISA) in matched Serum and CerebroSpinal Fluid (CSF) samples from patients with Neurological Diseases.
Patients with Relapsing/Remitting Multiple Sclerosis (RR-MS) had Serum and CSF MMP-9 levels comparable to those from patients with Inflammatory Neurological Diseases (INDs).
But, higher than patients with Non-Inflammatory Neurological Diseases (NINDs) and healthy donors (HDs).
MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity.
A correlation between the CSF/Serum Albumin (Q(AIb)) and CSF/Serum MMP-9 (Q(MMP-9)) was observed in IND and NIND but not in RR-MS patients.
Indicating that CSF MMP-9 levels in NIND and IND patents could be influenced by Serum MMP-9 and Blood-Brain Barrier (BBB) permeability properties.
MS patients had higher values of Q(MMP-9):Q(Alb)(MMP-9 index) than IND and NIND patients suggesting that in MS the increase in CSF MMP-9 could be due to Intrathecal synthesis of MMP-9.
A significant inverse correlation was found between MMP-9 and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both the increase in MMP-9 and the decrease in TIMP-1 Serum levels could contribute to BBB disruption and T-Lymphocyte entry into the CNS.
The Expression Profile Of Matrix MetalloProteinases (MMPs) And Their Inhibitors (TIMPs) In Lesions And Normal-Appearing White Matter Of Multiple Sclerosis
Raija L. P. Lindberg, Corline J. A. De Groot, Lisette Montagne, Peter Freitag, Paul van der Valk, Ludwig Kappos and David Leppert
Brain, Vol. 124, No. 9, 1743-1753, September 2001
University Hospitals, Departments of Research and Neurology, Basel, Switzerland and; University Hospital Vrije Universiteit, MS Centre for Research and Care, Division of NeuroPathology, Department of Pathology, The Netherlands
In Multiple Sclerosis, Matrix MetalloProteinases (MMPs) are effectors of crucial pathogenetic steps, such as Blood-Brain Barrier breakdown, invasion of Brain Parenchyma by Immune Cells and DeMyelination.
However, only limited data are available on the types of MMPs induced in the course of Multiple Sclerosis, and on the role of their endogenous antagonists, the Tissue Inhibitors of MetalloProteinases (TIMPs).
We quantified the transcriptional expression of six MMPs and the four TIMPs in lesions and in Normal-Appearing White Matter (NAWM) from post-mortem Multiple Sclerosis Brain tissue by real-time polymerase chain reaction, and compared levels with those in Brain tissue from six control patients without Neurological Disease.
The mRNA expression of MMP-7 and -9, but not of other MetalloProteinases [MMP-2 and -3, and Tumour Necrosis Factor-alpha (TNF-)-converting-enzyme] was equally upregulated throughout all stages of lesion formation with active inflammation, and in most of matched NAWM tissue.
The transcription of Cytokines TNF-/ß and InterLeukin-2 (IL-2), known modulators of MMPs, was upregulated only in distinct stages of lesion formation, while their receptors were not induced at all.
Which suggests that additional signalling molecules participate in the sustained upregulation of MMP-7 and -9 in Multiple Sclerosis. None of the TIMPs showed a significant induction over baseline expression of controls.
We hypothesize that an imbalance between MMP and TIMP expression may cause a persistent ProteoLytic overactivity in Multiple Sclerosis, that may be a factor for continuous tissue destruction, and hence for Secondary disease progression.