Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis.
Summary
Inflammation triggers cathepsin K–mediated cleavage of angiopoietin-2 into 25 and 50 kDa fragments that antagonize Tie2, destabilizing endothelium in sepsis. Pharmacologic inhibition of cathepsin K (odanacatib) improved survival in murine sepsis, and circulating ANGPT2 fragments in patients associated with worse outcomes.
Key Findings
- Cathepsin K cleaves full-length 75 kDa ANGPT2 into 25 and 50 kDa C-terminal fragments that antagonize Tie2.
- Odanacatib (cathepsin K inhibitor) improved survival in distinct murine sepsis models.
- Circulating ANGPT2 fragments accumulated in septic patients and were associated with adverse outcomes.
- Full-length ANGPT2 improved survival only in the presence of cathepsin K inhibition; otherwise increased mortality.
Clinical Implications
Cathepsin K inhibitors and assays for ANGPT2 fragments could enable prognostication and targeted endothelial-stabilizing therapy in sepsis. Tie2 pathway modulation may be revisited with context-specific strategies.
Why It Matters
This mechanistic discovery links a specific protease to ANGPT2 functional switching and demonstrates druggability with survival benefit in vivo, offering a tractable target and biomarker for vascular dysfunction in sepsis.
Limitations
- Human data are observational; causality of ANGPT2 fragments for outcomes in patients is not established.
- Safety and efficacy of cathepsin K inhibition in clinical sepsis remain untested.
Future Directions
Develop clinical assays for ANGPT2 fragments, validate prognostic utility, and test cathepsin K/Tie2-targeted therapies in early-phase sepsis trials with endothelial phenotyping.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- III - Mechanistic translational study with animal experiments and supporting observational human biomarker analyses; no clinical intervention.
- Study Design
- OTHER