Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Martin Floer^*, Martin Götte, Martin K. Wild, Jan Heidemann^*, Ezeddin Salem Gassar, Wolfram Domschke^*, Ludwig Kiesel, Andreas Luegering^* and Torsten Kucharzik^*

From the Departments of Medicine B^* and Gynecology and Obstetrics, Muenster University Hospital, Muenster, and the Max-Planck-Institute for Molecular Biomedicine, Muenster, Germany

Syndecan-1 (Sdc1) plays a major role in wound healing and modulatesinflammatory responses. Sdc1 expression is reduced in lesionsof patients with ulcerative colitis. The aim of this study wasto investigate the role of Sdc1 in murine dextran sodium sulfate(DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient(knockout (KO)) and wild-type mice by oral administration of3% DSS. KO mice exhibited a significantly increased lethalityas compared with wild-type controls (61 versus 5%, P < 0.05).Impaired mucosal healing and prolonged recruitment of inflammatorycells in KO mice were accompanied by significant up-regulationof tumor necrosis factor- ${alpha}$ , CC chemokine ligand 3/macrophageinflammatory protein-1 ${alpha}$ , and vascular cell adhesion molecule-1,as determined by histological correlation between 0 and 15 daysafter colitis induction, TaqMan low-density array analysis,and quantitative real-time PCR. Treatment from days 7 through14 with enoxaparin, a functional analogue of the Sdc1 heparansulfate chains, significantly reduced lethality of KO mice dueto DSS-induced colitis, which was correlated with improved mucosalhealing. In vitro, Sdc1-deficient polymorphonuclear cells displayedincreased adhesion to endothelial cells and intercellular adhesionmolecule-1, and enoxaparin reverted adhesion to wild-type levels.Small interfering RNA-mediated knockdown of Sdc1 expressionresulted in reduced basic fibroblast growth factor-mediatedmitogen-activated protein kinase signaling and reduced Caco-2cell proliferation. We conclude that Sdc1 has a protective effectduring experimental colitis. The modification of missing Sdc1function by heparin analogues may emerge as a promising anti-inflammatoryapproach.