Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

Abstract

Osteopontin (OPN) is a matricellular cytokine present in most tissues and body fluids; it is known to modulate immune responses. In previous studies using the dextran sulfate sodium (DSS) acute colitis model, we found exacerbated tissue destruction and reduced repair in OPN-null (À/À) mice compared with wild-type (WT) controls. As OPN is normally present in milk, we hypothesized that administration of OPN may protect the intestines from the adverse effects of experimental colitis. A volume of 20 or 2 mg/ml bovine milk OPN, dissolved in drinking water, was given to mice 24 h before, and during administration of DSS. Clinical parameters of colitis and neutrophil functions were analyzed as previously reported. Orally administered OPN was absorbed and detected in the colon mucosa by immunohistochemistry. The 20 mg/ml OPN-and DSS-treated WT mice showed 37% less weight loss and reduced colon shortening and spleen enlargements than control mice (Po0.05). OPN administration also reduced the disease activity index, improved red blood cell counts, and reduced gut neutrophil activity compared with the DSS-treated WT mice that were not administered OPN (Po0.05). Immunohistochemical detection of F4/80-labelled cells (macrophages) was also less frequent. The level of transforming growth factor b1 (TGF-b1) was increased and the levels of pro-inflammatory mediators decreased in colon tissue samples of OPN-treated mice analyzed by ELISA. The reversal of experimental colitis parameters by exogenous OPN was not as robust in the OPN À/À mice. Administration of prokaryotic-expressed recombinant OPN and bovine serum albumin were ineffective. This study shows that administration of a physiological concentration of milk OPN in drinking water ameliorates the destructive host response in DSS-induced acute colitis.

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…However, studies addressing the role of Opn during DSS-induced colitis, another chemically induced model, have been contradictory (14,15,(60)(61)(62)(63). Opn deficiency in Black Swiss mice was protective (15), whereas Opn deficiency in C57BL/6 mice resulted in increased intestinal tissue destruction (60) (61) found that Opn was anti-inflammatory during acute DSS colitis but proinflammatory during chronic DSS colitis.…”

Osteopontin Mediates Citrobacter rodentium-Induced Colonic Epithelial Cell Hyperplasia and Attaching-Effacing Lesions

“…Recent attempts to define a role for OPN in intestinal inflammation, using a chemically induced model of colitis (DSS), have yielded conflicting results. While our group has shown that OPN Ϫ/Ϫ mice are more susceptible to DSS colitis, through a reduction in tumor necrosis factor-␣ and neutrophil recruitment, 10,12 other investigators found an opposite effect. 9 More recently, Heilmann et al 11 found that OPN Ϫ/Ϫ mice are more susceptible to acute challenge with DSS, associated with reduced IL-22 and macrophage activity but increased serum tumor necrosis factor-␣, while chronic DSS-induced colitis was reduced in these mice.…”

“…In contrast, addition of topical OPN through rectal administration in OPN Ϫ/Ϫ mice did restore effects of C. rodentium infection, possibly because OPN may be differentially processed and internalized in the in vivo setting. The ability of exogenous OPN to be absorbed and attenuate DSS-induced colitis 12 supports a potential use for this compound in future research.…”

“…Although rectal delivery of exogenous OPN did not completely restore crypt length to levels observed in infected wild-type mice (Figure 2B), these results confirm a role for OPN in mediating epithelial cell responses to C. rodentium infection. In contrast, oral administration of OPN to infected OPN Ϫ/Ϫ mice 12 did not increase crypt length (data not shown), possibly due to intraluminal degradation of exogenous protein.…”

Osteopontin (OPN) Gene Polymorphisms and Autoimmune Diseases

“…It has been demonstrated that serum OPN level is elevated in IBD patients and correlates with disease activity [87][88][89][90][91]. However, some studies in humans and in animal models of colitis gave opposite results, suggesting a dual or protective function of OPN in intestinal inlammation [86,[91][92][93][94][95][96][97][98][99].…”