Colocalization with MMP-7 in the Distal Colon is Crucial for Syndecan-2 Shedding in Dextran Sulfate Sodium-Induced Colitis Mice

Abstract

Introduction Syndecan-2 expression is elevated during chronic inflammation and cancer development, and its shedding is observed in cancer patients. However, it remained unknown whether inflammation triggers syndecan-2 shedding. Methods The colitis model was produced in C57BL/6 mice by oral administration of 2–3% dextran sulfate sodium (DSS) in the drinking water. Syndecan-2 and MMP-7 expression levels in tissues and cells were detected by real-time PCR, Western blotting, and immunohistochemistry. Shed syndecan-2 levels were detected by slot blotting. For tissue culture, colon tissues were divided into proximal, transverse, and distal parts, and incubated in culture media. Results In C57BL/6 mice with DSS-induced colitis, syndecan-2 shedding began to increase after week 12 of chronic inflammation and continued to increase at week 15. The level of shed syndecan-2 correlated with the colocalization of syndecan-2 and MMP-7 in distal colon tissues. The mRNA expression of IL-6 was increased specifically in trans-distal colon tissues from weeks 9 to 15. IL-6 induced syndecan-2 expression and shedding and MMP-7 expression in ex vivo-cultured distal colon tissues and adenoma cell lines derived from the distal colon. IL-6 treatment induced STAT3 phosphorylation and MMP-7 expression in DLD-1 cells. The application of MMP-7 to ex vivo-cultured colon tissues increased the shedding of syndecan-2 to the culture medium. Conclusion Our findings suggest that chronic inflammation induces syndecan-2 shedding via the site-specific colocalization of syndecan-2 with MMP-7 in the distal colon.

Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7

“…found a strong positive correlation between MMP-7 expression in the glandular epithelium and the location of the lesion in both UC and CD patients ( 34 ). It has also been reported that MMP-7 expression levels vary along the colon ( 36 ), which is supported by our IHC data also showing differential MMP-7 levels in different areas of the colon. However, the origin of MMP-7 in the inflamed colon has not been fully characterized, partly because MMP-7 is a secreted protein with a relatively short half-life.…”

“…It is worth noting that smooth muscle cells, the predominant cell type in the intestine, also express MMP-7 in response to IL-4 and IL-13, which might contribute to IBD complications like perforation or fistula. Surprisingly, IL-6, which was reported to have an important role in MMP-7 expression in colonocytes ( 36 , 40 ), had no effect on MMP-7 expression in our cells. Further research is required to address this discrepancy.…”