title: Retracted: Glycogen synthase kinase-3beta inhibition attenuates the degree of arthritis caused by type II collagen in the mouse.
abstract: Recently, glycogen synthase kinase-3 (GSK-3) has being identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of arthritis caused by type II collagen (CII) in the mouse (collagen-induced arthritis; CIA). Mice developed erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund's adjuvant (CFA). The incidence of CIA was 100% by day 28 in the CII-challenged mice and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of mice with the GSK-3beta inhibitor TDZD-8 (1 mg/kg/day i.p.) starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26-35 and improved histological status in the joint and paw. Immunohistochemical analysis for nitrotyrosine, poly(ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) revealed a positive staining in inflamed joints from mice subjected to CIA. The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 was significantly reduced in CII-challenged mice treated with the GSK-3beta inhibitor. Plasma levels of tumor necrosis factor (TNF)-alpha and the joint tissue levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 were also significantly reduced by GSK-3beta inhibition. These data demonstrate that GSK-3beta inhibition exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.
authors.affiliation: Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi-98100 Messina, Italy. salvator@unime.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Laura
authors.initials: L
authors.lastname: Dugo
authors.forename: Marika
authors.initials: M
authors.lastname: Collin
authors.forename: Domenico
authors.initials: D
authors.lastname: Britti
authors.forename: Achille P
authors.initials: AP
authors.lastname: Caputi
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D024043:Collagen Type II; D051546:Cyclooxygenase 2 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D006614:Hindlimb / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D019402:Macrophage Inflammatory Proteins / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D015846:Monokines / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011859:Radiography; D013830:Thiadiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000276:immunology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D024043:Collagen Type II; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3