Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism

Wang, Xinyu; Chen, Shenghui; Wang, Jinghua; Chen, Yishu; Guo, Yanjun; Wang, Qinqiu; Liu, Zhening; Zeng, Hang; Xu, Chengfu

doi:10.7150/ijbs.80441

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International Journal of Medical Sciences

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Int J Biol Sci 2023; 19(7):2150-2166. doi:10.7150/ijbs.80441 This issue Cite

Research Paper

Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism

Xinyu Wang^*, Shenghui Chen^*, Jinghua Wang, Yishu Chen, Yanjun Guo, Qinqiu Wang, Zhening Liu, Hang Zeng, Chengfu Xu^✉

Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
* Contributed equally

Citation:

Wang X, Chen S, Wang J, Chen Y, Guo Y, Wang Q, Liu Z, Zeng H, Xu C. Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism. Int J Biol Sci 2023; 19(7):2150-2166. doi:10.7150/ijbs.80441. https://www.ijbs.com/v19p2150.htm

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Abstract

Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis.

Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored.

Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression.

Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.

Keywords: Ulcerative colitis, olfactomedin-4, matrix metalloproteinase-9, apoptosis

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APA

Wang, X., Chen, S., Wang, J., Chen, Y., Guo, Y., Wang, Q., Liu, Z., Zeng, H., Xu, C. (2023). Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism. International Journal of Biological Sciences, 19(7), 2150-2166. https://doi.org/10.7150/ijbs.80441.

ACS

Wang, X.; Chen, S.; Wang, J.; Chen, Y.; Guo, Y.; Wang, Q.; Liu, Z.; Zeng, H.; Xu, C. Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism. Int. J. Biol. Sci. 2023, 19 (7), 2150-2166. DOI: 10.7150/ijbs.80441.

NLM

CSE

Wang X, Chen S, Wang J, Chen Y, Guo Y, Wang Q, Liu Z, Zeng H, Xu C. 2023. Olfactomedin-4 deletion exacerbates DSS-induced colitis through a matrix metalloproteinase-9-dependent mechanism. Int J Biol Sci. 19(7):2150-2166.

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