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MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a.

ABSTRACT: B cells are necessary to maintain disease activity in relapsing multiple sclerosis (MS) and produce matrix metallopeptidase-9 (MMP-9), which disrupts the blood-brain barrier. MMP-9 protein expression was increased and expression of microRNA-320a (miR-320a), which targets MMP-9 mRNA, was significantly decreased in B lymphocytes of MS patients during a disease relapse compared to remission. Functional significance of these findings was demonstrated by transfecting human B lymphocytes with miR-320a inhibitor, which led to increased MMP-9 expression and secretion. In summary, expression of miR-320a is decreased in B cells of MS patients and may contribute to increased blood-brain barrier permeability and neurological disability.

SUBMITTER: Aung LL

PROVIDER: S-EPMC4297694 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a.

Aung Latt Latt LL Mouradian M Maral MM Dhib-Jalbut Suhayl S Balashov Konstantin E KE

Journal of neuroimmunology 20141110

B cells are necessary to maintain disease activity in relapsing multiple sclerosis (MS) and produce matrix metallopeptidase-9 (MMP-9), which disrupts the blood-brain barrier. MMP-9 protein expression was increased and expression of microRNA-320a (miR-320a), which targets MMP-9 mRNA, was significantly decreased in B lymphocytes of MS patients during a disease relapse compared to remission. Functional significance of these findings was demonstrated by transfecting human B lymphocytes with miR-320a ...[more]

PMID: 25468268

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Project description:BACKGROUND:Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). METHODS:We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts. RESULTS:Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively. CONCLUSIONS:Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). FUNDING:This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

Dataset Information

MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a.

Publications

MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a.

Similar Datasets

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