Association between matrix Gla protein and ulcerative colitis according to DNA microarray data

Abstract

Background Matrix Gla protein (MGP) is a secreted protein contributed to the immunomodulatory functions of mesenchymal stromal cells. Microarray profiling found a significantly higher expression level of the extracellular matrix gene MGP in patients with ulcerative colitis (UC). However, little is known about the role of MGP in UC and its upstream signaling regulation. This study aimed to identify the expression of MGP in UC and its upstream regulator mechanism. Methods Colonic mucosa biopsies were obtained from patients with UC and healthy controls. DNA microarray profiling was used to explore underlying genes correlating with UC development. Mice were fed with water containing different concentrations of dextran sodium sulfate (DSS) to induce an experimental colitis model. Colonic tissues were collected and evaluated using immunohistochemistry, immunoblot, real-time polymerase chain reaction, and chromatin immunoprecipitation assay. Bioinformatics analysis was performed to identify candidate MGP gene-promoter sequence and transcription-initiation sites. Luciferase-reporter gene assay was conducted to examine the potential transcription factor of MGP gene expression. Results The expression of MGP was significantly increased in colonic tissues from UC patients and DSS-induced colitis models, and was positively correlated with disease severity. Bioinformatics analysis showed a conserved binding site for Egr-1 in the upstream region of human MGP gene. The significantly higher level of Egr-1 gene expression was found in UC patients than in healthy controls. The activity of luciferase was significantly enhanced in the Egr-1 expression plasmid co-transfected group than in the control group and was further inhibited when co-transfected with the Egr-1 binding-site mutated MGP promoter. Conclusions Up-regulated expression of MGP was found in UC patients and DSS-induced colitis. The expression of MGP can be regulated by Egr-1.

Inactive matrix Gla protein is elevated in patients with inflammatory bowel disease

“…Our findings could be implying that increased IBD activity up regulates MGP through complex inflammatory mechanisms, but due to possible vitamin K deficiency, the peptide cannot be fully activated and therefore loses its inhibitory effect on vascular calcification. This would be in line with the results of a Danish cohort study, which reported that flares and persistent IBD activity increases the risk of myocardial infarction, stroke and cardiovascular death[ 49 ], and the previously mentioned study on UC patients which showed that the expression of MGP mRNA increases with the disease severity[ 24 ]. Moreover, after division of patients with IBD into tertiles depending on hsCRP levels and FC levels our study showed in both cases significantly higher plasma levels of dp-ucMGP in the 3 rd tertile compared to the 1 st and 2 nd tertiles which further indicates the possible association of dp-ucMGP with the IBD activity.…”

“…Given results are in line with the outcomes of a recent study conducted on human patients with UC and on mice with dextran sulfate sodium (DSS) induced colitis[ 24 ]. They showed that MGP mRNA levels are significantly higher in both UC patients and DSS-induced colitis mice compared to their control groups.…”

Microbiota, not host origin drives ex vivo intestinal epithelial responses

“… 38–41 Dong et al found increased gene expression and activation levels of EGR1 in biopsies from UC patients, compared to healthy controls. 42 Also MYC, another top three transcription factors, was found at higher levels in biopsies from patients with IBD by Macpherson et al and linked to altered cell cycle control due to inflammatory processes. 43 …”

Role of Vitamin K in Intestinal Health

“…Compared to the healthy control group, plasma levels of dp-ucMGP were significantly higher in IBD patients and positively correlated with high sensitivity C-reactive protein (hsCRP) levels ( 221 ). The expression of MGP, which can be upregulated by a conserved binding site for Egr-1 in the upstream region of the human MGP gene, was positively correlated with disease severity of UC patients and DSS-induced colitis rats ( 222 ). MGP was upregulated in different stages of colon cancer and associated with a worse prognosis ( 223 ).…”