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IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS
E Waubant1, D Goodkin, A Bostrom
1UCSF Multiple Sclerosis Center, University of California, San Francisco 94117, USA. waubant@itsa.ucsf.edu
Objective:
To 1)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; 2)determine the relationship between these serum levels and MRI activity; and 3) evaluate the effect of interferon (IFN) therapy on these measures.
Background:
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.
Methods:
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 IFNbeta-1b.
Results:
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 IFNbeta 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). IFNbeta did not influence levels of MMP-2 and TIMP-2.
Conclusion:
The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNbeta-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
Insights
The MMP-9/TIMP-1 ratio may predict MRI activity in secondary progressive multiple sclerosis (SPMS). Interferon-beta-1b therapy may reduce new gadolinium-enhancing lesions by altering this ratio.
Area of Science:
- Neuroimmunology
- Biomarker Discovery
- Multiple Sclerosis Pathogenesis
Background:
- Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) serum levels are implicated in multiple sclerosis (MS) lesion development.
- Elevated MMP-9 and reduced TIMP-1 predict new gadolinium-enhancing (Gd+) lesions in relapsing-remitting MS (RRMS).
Purpose of the Study:
- To determine serum levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in patients with secondary progressive multiple sclerosis (SPMS).
- To correlate these serum levels with MRI-detected disease activity.
- To evaluate the impact of interferon (IFN) therapy on these biomarkers and MRI activity.
Main Methods:
- Serum samples from 33 SPMS patients in a phase III study of IFNbeta-1b were analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals.
- Monthly brain MRI scans were performed to detect new gadolinium-enhancing (Gd+) lesions over up to 3 years.
- Statistical analyses were used to correlate biomarker levels and ratios with MRI activity and treatment effects.
Main Results:
- Patients with new Gd+ lesions exhibited significantly higher MMP-9 levels compared to those without (median 351 vs 226 ng/mL, p=0.049).
- The MMP-9/TIMP-1 ratio predicted new Gd+ lesions on concurrent (p=0.052) and subsequent scans (p=0.048).
- IFNbeta recipients showed higher TIMP-1 levels and a trend towards lower MMP-9 levels compared to placebo, suggesting a modulation of the MMP-9/TIMP-1 ratio.
Conclusions:
- The MMP-9/TIMP-1 ratio serves as a potential predictor of MRI-evident disease activity in SPMS.
- IFNbeta-1b treatment may exert its therapeutic effect in MS, partly by favorably altering the MMP-9/TIMP-1 ratio.
- MMP-2 and TIMP-2 levels were not significantly influenced by IFNbeta therapy.