title: Osteopontin mediates Citrobacter rodentium-induced colonic epithelial cell hyperplasia and attaching-effacing lesions.
abstract: Although osteopontin (OPN) is up-regulated in inflammatory bowel diseases, its role in disease pathogenesis remains controversial. The objective of this study was to determine the role of OPN in host responses to a non-invasive bacterial pathogen, Citrobacter rodentium, which serves as a murine infectious model of colitis. OPN gene knockout and wild-type mice were infected orogastrically with either C. rodentium or Luria-Bertani (LB) broth. Mouse-derived OPN(+/+) and OPN(-/-) fibroblasts were incubated with C. rodentium and attaching-effacing lesions were demonstrated using transmission electron microscopy and immunofluorescence. Colonic expression of OPN was increased by C. rodentium infection of wild-type mice. Furthermore, colonic epithelial cell hyperplasia, the hallmark of C. rodentium infection, was reduced in OPN(-/-) mice, and spleen enlargement by infection was absent in OPN(-/-) mice. Rectal administration of OPN to OPN(-/-) mice restored these effects. There was an 8- to 17-fold reduction in bacterial colonization in OPN(-/-) mice, compared with wild-type mice, which was accompanied by reduced attaching-effacing lesions, both in infected OPN(-/-) mice and OPN(-/-) mouse fibroblasts. Moreover, adhesion pedestals were restored in OPN(-/-) cells complemented with human OPN. Therefore, lack of OPN results in decreased pedestal formation, colonization, and colonic epithelial cell hyperplasia responses to C. rodentium infection, indicating that OPN impacts disease pathogenesis through bacterial attachment and altered host immune responses.
authors.affiliation: Pediatric Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Eytan
authors.initials: E
authors.lastname: Wine
authors.forename: Grace
authors.initials: G
authors.lastname: Shen-Tu
authors.forename: Mélanie G
authors.initials: MG
authors.lastname: Gareau
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Goldberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Licht
authors.forename: Bo-Yee
authors.initials: BY
authors.lastname: Ngan
authors.forename: Esben S
authors.initials: ES
authors.lastname: Sorensen
authors.forename: James
authors.initials: J
authors.lastname: Greenaway
authors.forename: Jaro
authors.initials: J
authors.lastname: Sodek
authors.forename: Ron
authors.initials: R
authors.lastname: Zohar
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sherman
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D006965:Hyperplasia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000378:metabolism*
chemical_list: D053495:Osteopontin