Repurposed anticoagulant dabigatran hits BIG2 to curb TNF and IL-1 signaling in osteoarthritis
- A screen of approved drugs flagged dabigatran, a thrombin inhibitor, as a suppressor of both TNF-α and IL-1β signaling that restored chondrocyte metabolism.
- Pulldown with mass spectrometry identified BIG2 as its binding target; engagement promotes TNFR1 release and autophagy-lysosome degradation of IL-1R1.
- In mouse and cynomolgus macaque osteoarthritis models, treatment reduced cartilage degeneration and pain and improved joint function.
💡 Points Based on the abstract
Dabigatran's day job is thrombin inhibition, so the decisive control is genetic: does BIG2 knockdown abolish the benefit, and does a thrombin-inactive analog keep it? Also unclear is whether cartilage exposure at a tolerable dose reaches in vitro concentrations. Chronic anticoagulant dosing for a non-lethal disease leaves little bleeding margin, so a BIG2-selective derivative is the sensible next step.
📄 Paper · Science Translational Medicine ↗ Dual inhibition of TNF-α and IL-1β signaling through BIG2 ameliorates osteoarthritis in mouse and primate models