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Therapeutically, both the myeloid-specific knockout of neutrophil elastase and the pharmacological inhibition using a clinically applied drug (sivelestat) alleviated joint degeneration in naturally aging mice partly by reducing elastin fragments levels. The pharmacological inhibitor exhibited 1-y systemic safety in dogs and alleviated osteoarthritis-like phenotypes in naturally aging dogs and human explants. Finally, several matrix fragments, including the fragments of type II collagen, fibronectin, hyaluronic acid, and aggrecan, were demonstrated to universally induce cartilage degeneration. Conclusively, this study identifies degraded matrix, especially elastin fragments, as one of the drivers of joint degeneration via pathological macrophage\u2013chondrocyte crosstalk, suggesting elastase inhibitors as a potential therapeutic strategy for aging-related osteoarthritis.<\/jats:p>","DOI":"10.1073\/pnas.2537622123","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:38:23Z","timestamp":1783532303000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of elastin degradation alleviates joint degeneration in aging mice, dogs, and human models"],"prefix":"10.1073","volume":"123","author":[{"given":"Junzhi","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Li Dak Sum and Yip Yio Chin Center for 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