Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse

Salvatore Cuzzocrea, Emanuela Mazzon, Rosanna Di Paola, Carmelo Muià, Concetta Crisafulli, Laura Dugo, Marika Collin, Domenico Britti, Achille P. Caputi, Christoph Thiemermann

Research output: Contribution to journalArticle

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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-3β 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-3β 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-3β inhibitor. Plasma levels of tumor necrosis factor (TNF)-α and the joint tissue levels of macrophage inflammatory protein (MIP)-1α and MIP-2 were also significantly reduced by GSK-3β inhibition. These data demonstrate that GSK-3β inhibition exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.

Original languageEnglish
Pages (from-to)57-67
Number of pages11
JournalClinical Immunology
Volume120
Issue number1
DOIs
Publication statusPublished - Jul 2006

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Glycogen Synthase Kinase 3
Collagen Type II
Arthritis
Joints
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Chemokine CXCL2
Staining and Labeling
Poly Adenosine Diphosphate Ribose
Macrophage Inflammatory Proteins
Experimental Arthritis
Freund's Adjuvant
Protein-Serine-Threonine Kinases
Bone Resorption
Emulsions
Cartilage
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha
Inflammation
Incidence

Keywords

  • Collagen
  • GSK-3β
  • Inflammation
  • MIP-2
  • MIP-lα
  • Peroxynitrite
  • TDZD-8
  • TNF-α

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. / Cuzzocrea, Salvatore; Mazzon, Emanuela; Di Paola, Rosanna; Muià, Carmelo; Crisafulli, Concetta; Dugo, Laura; Collin, Marika; Britti, Domenico; Caputi, Achille P.; Thiemermann, Christoph.

In: Clinical Immunology, Vol. 120, No. 1, 07.2006, p. 57-67.

Research output: Contribution to journalArticle

Cuzzocrea, S, Mazzon, E, Di Paola, R, Muià, C, Crisafulli, C, Dugo, L, Collin, M, Britti, D, Caputi, AP & Thiemermann, C 2006, 'Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse', Clinical Immunology, vol. 120, no. 1, pp. 57-67. https://doi.org/10.1016/j.clim.2006.03.005
Cuzzocrea, Salvatore ; Mazzon, Emanuela ; Di Paola, Rosanna ; Muià, Carmelo ; Crisafulli, Concetta ; Dugo, Laura ; Collin, Marika ; Britti, Domenico ; Caputi, Achille P. ; Thiemermann, Christoph. / Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. In: Clinical Immunology. 2006 ; Vol. 120, No. 1. pp. 57-67.
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