In vitro target validation and in vivo efficacy of p38 MAP kinase inhibition in established chronic collagen-induced arthritis model: a pre-clinical study

Objectives: The aim of the present study was to determine the in vivo efficacy of p38 mitogen-activated protein kinase (MAPK) inhibitors, namely GW856553X and GSK678361, in murine models of arthritis.

Methods: The effect of p38 MAPK inhibitors was tested in 2 variants of the collagen-induced arthritis model (CIA) in DBA/1 mice, acute arthritis induced by heterologous collagen and chronic relapsing arthritis induced by homologous collagen. Animals were treated after onset of arthritis. Furthermore, post-onset disease efficacy of GSK678361 was tested in the chronic model, so as to determine the effects on established arthritis. In vitro studies were carried out with GW856553X, using human umbilical vein endothelial cells, to determine potential effects of GW856553X on the vasculature.

Results: In both acute and chronic arthritis, GW856553X reduced signs and symptoms of disease, and protected joints from damage. The effect of GW856553X in chronic CIA was confirmed using an alternative compound, GSK678361. Importantly, treatment with GSK678361 from 14 days post-onset of chronic arthritis completely reversed signs of established disease and joint destruction. Mechanism of action studies demonstrated that GW856553X inhibited endothelial cell migration and angiogenesis in vitro, with reduced pro-inflammatory cytokine production.

Conclusions: Suppression of murine CIA by the p38 MAPK inhibitors GW856553X and GSK678361 suggests that they may have therapeutic potential for future use in RA if safe clinical dosing achieves adequate compound exposure.

Comments：

The present study aimed to investigate the effectiveness of two p38 MAPK inhibitors, GW856553X and GSK678361, in treating murine models of arthritis. The study utilized two variants of the collagen-induced arthritis model in DBA/1 mice, acute arthritis induced by heterologous collagen and chronic relapsing arthritis induced by homologous collagen.

The results showed that GW856553X reduced the signs and symptoms of disease in both acute and chronic arthritis and protected joints from damage. In chronic arthritis, GSK678361 was also found to be effective in treating established disease, completely reversing signs of established disease and joint destruction when treatment was initiated 14 days post-onset.

Mechanism of action studies revealed that GW856553X inhibited endothelial cell migration and angiogenesis in vitro, resulting in reduced pro-inflammatory cytokine production.

These findings suggest that p38 MAPK inhibitors have therapeutic potential for the treatment of rheumatoid arthritis (RA) if safe clinical dosing achieves adequate compound exposure.

Related Products

Cat.No.	Product Name	Information
S7215	Losmapimod	Losmapimod is a selective, potent, and orally active p38 MAPK inhibitor with pKi of 8.1 and 7.6 for p38α and p38β, respectively. P38 MAPKs are involved in cell differentiation, apoptosis and autophagy. Phase 3.

Related Targets

Autophagy Apoptosis related p38 MAPK