Treatment of collagen-induced arthritis rat model by using Notch signalling inhibitor
Jianhai Chen1,2, Jian Li1,2, Jinqing Chen3
1Center for Translational Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
Background:
The Notch signalling pathway has been reported to play a key role in rheumatoid arthritis (RA) development. Thus, inhibition of the activation of this signalling pathway may be a promising approach to the treatment of RA. In this study, the Notch signalling inhibitor LY411575, which can inhibit both Notch1 and Notch3, was used for the treatment of collagen-induced arthritis (CIA) rats.
Methods:
Wistar rats were immunised with bovine type II collagen (CII) to establish rats CIA model. The inhibitory effects of LY411575 on Notch1 intracellular domain (N1ICD) and Notch3 intracellular domain (N3ICD) protein was verified by western blot (WB) in vitro. CIA rats were treated with different doses of LY411575 for 15 and 28 days, respectively. Methotrexate and sodium carboxymethyl cellulose (CMC-Na) were used as positive and negative (vehicle) control respectively. Destruction of the rat ankle joint and the bone loss on the periarticular side were evaluated by micro-computed tomography (Micro-CT). In addition, destruction of the ankle articular cartilage and the osteoclast numbers were determined by histology. Expression of N1ICD and N3ICD in the ankle joint was detected by immunohistochemistry.
Results:
LY411575 could significantly inhibit the expression of N1ICD and N3ICD in vitro. Micro-CT test showed that the ankle joint destruction significantly improved after treatment with LY411575 (5 mg/kg and 10 mg/kg, respectively). The bone quality in the LY411575 (5 mg/kg and 10 mg/kg, respectively) groups were improved compared with the vehicle group. Histological analysis showed that LY411575 (5 mg/kg and 10 mg/kg, respectively) treatment reduced the severity of ankle joint inflammation in CIA rats (including ankle joint destruction, pannus formation, and cartilage damage) and reduced the expression of N1ICD and N3ICD in CIA rats ankle joints significantly.
Conclusion:
The inhibitor of Notch signalling LY411575 is an effective treatment for CIA.
The Translational Potential Of This Article:
Our study provides new evidence to support the potential clinical application of Notch signalling pathway inhibitor LY411575 as a drug candidate for the treatment of RA.
Insights
The Notch signalling inhibitor LY411575 effectively treated collagen-induced arthritis in rats. This study supports LY411575 as a potential therapeutic agent for rheumatoid arthritis.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- The Notch signalling pathway is implicated in the pathogenesis of rheumatoid arthritis (RA).
- Inhibiting Notch signalling presents a potential therapeutic strategy for RA treatment.
- LY411575, a dual inhibitor of Notch1 and Notch3, was investigated for its efficacy in a rat model of RA.
Purpose of the Study:
- To evaluate the therapeutic potential of the Notch signalling inhibitor LY411575 in a collagen-induced arthritis (CIA) rat model.
- To assess the effects of LY411575 on joint destruction, inflammation, and Notch pathway activation in CIA rats.
Main Methods:
- A collagen-induced arthritis (CIA) rat model was established using Wistar rats immunized with bovine type II collagen.
- The inhibitory effect of LY411575 on Notch1 and Notch3 intracellular domains was confirmed in vitro using western blot.
- CIA rats were treated with varying doses of LY411575, with methotrexate as a positive control and CMC-Na as a vehicle control.
- Joint destruction and bone loss were assessed using micro-computed tomography (Micro-CT), while histological analysis evaluated cartilage damage and osteoclast numbers.
- Immunohistochemistry was used to detect the expression of Notch1 and Notch3 intracellular domains in ankle joints.
Main Results:
- LY411575 demonstrated significant inhibition of Notch1 and Notch3 intracellular domain expression in vitro.
- Treatment with LY411575 (5 and 10 mg/kg) significantly improved ankle joint destruction and bone quality in CIA rats compared to the vehicle group.
- Histological analysis revealed that LY411575 treatment reduced ankle joint inflammation, including pannus formation and cartilage damage, and significantly decreased Notch1 and Notch3 intracellular domain expression in CIA rat ankle joints.
Conclusions:
- The Notch signalling inhibitor LY411575 is an effective treatment for collagen-induced arthritis in rats.
- These findings provide evidence for the potential clinical application of LY411575 as a therapeutic agent for rheumatoid arthritis.
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