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Hema Aluri, Claire Kublin, Suharika Thotakura, Paul Leavis, Helen P Makarenkova, Driss Zoukhri; Inhibition of matrix metalloproteinases 2 and 9 activity improves tear production in mouse models of Sjögren’s Syndrome. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4912.
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© ARVO (1962-2015); The Authors (2016-present)
In Sjögren’s disease, chronic inflammation in the lacrimal gland results in changes in the composition of extracellular matrix (ECM) which compromises tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP2 and 9, by inflammatory cells invading the lacrimal gland modifies the ECM environment therefore disrupting tissue repair. In the present study, we tested this hypothesis.
MRL/lpr (female, 12 week old) and NOD (male, 13 week old) mice were used in this study (n=4-5). Age and gender matched MRL/++ and BALB/c mice served as controls, respectively. The lacrimal glands were harvested and divided into three pieces. One piece was fixed and processed for histology and immunohistochemistry. Another piece was homogenized and cell lysates were used for zymography or western blotting. Total RNA was isolated from the third piece and used for qPCR or microarray analyses. In another study, MRL/lpr mice (female, 9 week old) were treated with a selective MMP2/9 inhibitor peptide (CTT peptide) or a control peptide (STT peptide) (n=4, 100 µg/mouse, i.p. daily for 5 weeks). Tear production was measured, each week using phenol red impregnated threads. At the end of treatment, the lacrimal glands were excised and processed as described above.
MMP-2 and -9 activities as measured by zymography were significantly up-regulated in the lacrimal glands of MRL/lpr and NOD mice, compared to controls. Immunohistochemical analysis showed that MMP-2 and -9 protein expression levels were increased in diseased mice. Also, there was a 3-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice (p<0.05). Microarray analyses showed that NOD and MRL/lpr mice had very similar patterns of integrins expression in the lacrimal glands. Following five weeks of treatment with the MMP2/9 inhibitor, MRL/lpr mice showed a 2-fold increase in tear production compared to baseline (day 0). In addition, MMP-2 and -9 activities were significantly down-regulated in the MRL/lpr mice treated with MMP2/9 inhibitor compared to mice treated with control peptide.
We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren’s syndrome. Our data also suggest that manipulation of MMP2/9 might be a potential therapeutic target to increase tear production in inflamed lacrimal gland.
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