Retracted: Glycogen synthase kinase-3beta inhibition attenuates the degree of arthritis caused by type II collagen in
Salvatore Cuzzocrea1, Emanuela Mazzon, Rosanna Di Paola
1Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi-98100 Messina, Italy. salvator@unime.it
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.
Insights
Inhibition of glycogen synthase kinase-3 beta (GSK-3beta) reduced inflammation and tissue damage in collagen-induced arthritis (CIA) mouse models. This suggests GSK-3beta inhibition is a potential therapeutic strategy for chronic inflammatory diseases.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Glycogen synthase kinase-3 (GSK-3) is a key serine-threonine protein kinase involved in numerous cellular functions.
- GSK-3 plays a significant role in the development of various diseases, including inflammatory conditions.
Purpose of the Study:
- To evaluate the therapeutic potential of inhibiting GSK-3beta in a mouse model of collagen-induced arthritis (CIA).
- To investigate the impact of GSK-3beta inhibition on the progression and severity of arthritis and associated tissue damage.
Main Methods:
- Collagen-induced arthritis (CIA) was established in mice by immunization with type II collagen (CII).
- Mice were treated with a GSK-3beta inhibitor (TDZD-8) starting at the onset of arthritis.
- Clinical signs, radiographic bone resorption, joint histopathology, and levels of inflammatory markers (nitrotyrosine, PAR, iNOS, COX-2, TNF-alpha, MIP-1alpha, MIP-2) were assessed.
Main Results:
- GSK-3beta inhibition significantly ameliorated clinical arthritis symptoms and improved histological joint status.
- Treatment reduced the expression of key inflammatory mediators including nitrotyrosine, poly(ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2).
- Plasma levels of tumor necrosis factor-alpha (TNF-alpha) and joint tissue levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 were significantly decreased.
Conclusions:
- GSK-3beta inhibition demonstrates potent anti-inflammatory effects in chronic inflammatory conditions like CIA.
- Targeting GSK-3beta can effectively reduce tissue damage and ameliorate disease severity in arthritis.
- GSK-3beta inhibition represents a promising therapeutic avenue for managing chronic inflammatory diseases.
