Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis.

Summary

Inflammation-driven cathepsin K cleaves angiopoietin-2 into 25/50 kDa fragments that antagonize Tie2, destabilizing the endothelium in sepsis. Pharmacologic inhibition with odanacatib improved survival in murine models, and ANGPT2 fragments accumulated in septic patients and associated with worse outcomes.

Key Findings

• Macrophage-stimulated endothelial cells released ANGPT2 with loss of full-length 75 kDa form and emergence of 25/50 kDa C-terminal fragments.
• Cathepsin K was necessary and sufficient to generate ANGPT2 fragments that bound and antagonized Tie2.
• Odanacatib improved survival in murine sepsis; benefit depended on full-length ANGPT2 and was reversed by cANGPT225.
• Septic patients had circulating ANGPT2 fragments associated with adverse outcomes.

Clinical Implications

Cathepsin K inhibition (e.g., odanacatib) may stabilize endothelial Tie2 signaling in sepsis; circulating ANGPT2 fragments could stratify risk and guide therapy. This informs trials targeting the ANGPT2–Tie2 axis in inflammatory shock.

Limitations

• Human data are observational and cannot establish clinical efficacy of cathepsin K inhibition
• Safety and dosing of odanacatib in sepsis require dedicated trials

Future Directions

Prospective trials of cathepsin K inhibitors in septic shock with ANGPT2 fragment monitoring; development of clinical assays to quantify ANGPT2 fragments and patient stratification strategies.