Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice
Min-Chan Park1, Yong-Jin Kwon, Soo-Jin Chung
1Department of Internal Medicine, Division of Rheumatology, Yonsei University College of Medicine, Seoul, South Korea. mcpark@yuhs.ac
Objective:
Liver X receptors (LXRs) have been characterized as regulators of macrophage inflammatory pathways. Synthetic LXR agonists inhibit the macrophage response to bacterial pathogens and antagonize the induction of a number of pro-inflammatory genes. The aim of this study was to investigate the preventive effects of synthetic LXR agonist, GW3965, treatment on the evolution of arthritis and inflammatory response in a murine CIA model.
Methods:
Intradermal injection of bovine type II CIA in DBA/1 mice. Along with the induction of CIA, mice were treated with oral GW3965 (0.1, 0.3 or 1.0 mg/kg/day) or vehicle from Day 1 to Day 40. Clinical assessment for arthritis scores and histopathological assessment of joint sections were performed. The expression of inflammatory mediators was evaluated by immunohistochemical staining. Serum pro-inflammatory cytokine levels were determined using ELISA.
Results:
The CIA incidence was 100% on Day 27 and the severity progressed until Day 35 with histological features of cartilage erosion in vehicle-treated mice. GW3965 treatment significantly reduced the arthritis incidence and attenuated the clinical and histological severity, compared with vehicle-treated mice. GW3965 treatment also significantly reduced inflammatory mediator production in joint sections and serum pro-inflammatory cytokine levels in a dose-dependent manner.
Conclusions:
These results indicate that activation of LXRs suppresses the onset of CIA and reduces inflammation and joint destruction in CIA mice. The data could suggest that LXR treatment is an effective prophylactic approach to suppress the evolution of synovitis and resultant joint destruction observed in RA.
Insights
Synthetic Liver X receptor (LXR) agonist GW3965 treatment significantly reduced arthritis incidence and severity in a mouse model. This suggests LXR activation may be a promising prophylactic strategy for rheumatoid arthritis (RA) and joint destruction.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Liver X receptors (LXRs) regulate macrophage inflammatory pathways.
- Synthetic LXR agonists can inhibit inflammatory gene induction.
Purpose of the Study:
- To investigate the preventive effects of the synthetic LXR agonist GW3965 on arthritis development and inflammation in a collagen-induced arthritis (CIA) mouse model.
Main Methods:
- DBA/1 mice were induced with bovine type II collagen-induced arthritis (CIA).
- Mice received oral GW3965 (0.1–1.0 mg/kg/day) or vehicle from Day 1 to Day 40.
- Arthritis scores, histopathology, inflammatory mediator expression, and serum cytokine levels were assessed.
Main Results:
- GW3965 treatment significantly reduced CIA incidence, clinical severity, and histological joint damage.
- Inflammatory mediator production and serum pro-inflammatory cytokine levels were dose-dependently reduced by GW3965.
- Vehicle-treated mice showed 100% CIA incidence and progressive cartilage erosion.
Conclusions:
- LXR activation effectively suppresses CIA onset, inflammation, and joint destruction in mice.
- LXR agonist treatment shows potential as a prophylactic approach for rheumatoid arthritis (RA).
- This study highlights LXRs as therapeutic targets for inflammatory joint diseases.
