title: Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammation of the joints. RA has been shown to increase the morbidity of and mortality due to cardiovascular and cerebrovascular diseases. We recently reported that cerebrovascular permeability was increased in mice with collagen-induced arthritis (CIA), an animal model of RA. S100A4, a member of the S100 family, is up-regulated in synovial fluid and plasma from RA patients. This study was aimed at evaluating a role of S100A4 in the mediation of blood-brain barrier (BBB) dysfunction in CIA mice. CIA was induced by immunization with type II collagen in mice. Cerebrovascular permeability was assessed by measurement of sodium fluorescein (Na-F) levels in the brains of control and CIA mice. Serum S100A4 concentrations in control and CIA mice were measured by enzyme-linked immunosorbent assays (ELISA). Accumulation of Na-F in the brain and serum levels of S100A4 were increased in CIA mice. Increased S100A4 levels in the serum are closely correlated with hyperpermeability of the cerebrovascular endothelium to Na-F. We investigated whether S100A4 induces BBB dysfunction using mouse brain capillary endothelial cells (MBECs). S100A4 decreased the transendothelial electrical resistance and increased Na-F permeability in the MBECs. S100A4 reduced the expression of occludin, a tight junction protein, and stimulated p53 expression in MBECs. These findings suggest that S100A4 increases paracellular permeability of MBECs by decreasing expression levels of occludin, at least in part, via p53. The present study highlights a potential role for S100A4 in BBB dysfunction underlying cerebrovascular diseases in patients with RA.
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishioku
authors.forename: K
authors.initials: K
authors.lastname: Furusho
authors.forename: A
authors.initials: A
authors.lastname: Tomita
authors.forename: H
authors.initials: H
authors.lastname: Ohishi
authors.forename: S
authors.initials: S
authors.lastname: Dohgu
authors.forename: H
authors.initials: H
authors.lastname: Shuto
authors.forename: A
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D024043:Collagen Type II; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000097:blood*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D062826:Zonula Occludens-1 Protein
chemical_list: D024043:Collagen Type II; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C569043:Tjp1 protein, mouse; D016159:Tumor Suppressor Protein p53; D062826:Zonula Occludens-1 Protein