{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:03:39Z","timestamp":1792047819724,"version":"4.4.0"},"reference-count":59,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":43,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,15]]},"abstract":"<jats:p>\n                    Elevated angiopoietin-2 is associated with diverse inflammatory conditions, including sepsis, a leading global cause of mortality. During inflammation, angiopoietin-2 antagonizes the endothelium-enriched receptor Tie2 to destabilize the vasculature. In other contexts, angiopoietin-2 stimulates Tie2. The basis for context-dependent antagonism remains incompletely understood. Here, we show that inflammation-induced proteolytic cleavage of angiopoietin-2 converts this ligand from Tie2 agonist to antagonist. Conditioned media from stimulated macrophages induced endothelial angiopoietin-2 secretion. Unexpectedly, this was associated with reduction of the 75 kDa full-length protein and appearance of new 25 and 50 kDa C-terminal fragments. Peptide sequencing proposed cathepsin K as a candidate protease. Cathepsin K was necessary and sufficient to cleave angiopoietin-2. Recombinant 25 and 50 kDa angiopoietin-2 fragments (cANGPT2\n                    <jats:sub>25<\/jats:sub>\n                    and cANGPT2\n                    <jats:sub>50<\/jats:sub>\n                    ) bound and antagonized Tie2. Cathepsin K inhibition with the phase 3 small-molecule inhibitor odanacatib improved survival in distinct murine sepsis models. Full-length angiopoietin-2 enhanced survival in endotoxemic mice administered odanacatib and, conversely, increased mortality in the drug\u2019s absence. Odanacatib\u2019s benefit was reversed by heterologous cANGPT2\n                    <jats:sub>25<\/jats:sub>\n                    . Septic humans accumulated circulating angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of angiopoietin-2 from Tie2 agonist to antagonist, with therapeutic implications for inflammatory conditions associated with angiopoietin-2 induction.\n                  <\/jats:p>","DOI":"10.1172\/jci174135","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T12:00:22Z","timestamp":1741003222000},"source":"Crossref","is-referenced-by-count":10,"title":["Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis"],"prefix":"10.1172","volume":"135","author":[{"given":"Takashi","family":"Suzuki","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Loyde","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of 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