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Yet, the nano\u2010micro scale spatiotemporal pathological progression, especially its original site and actuating events during OA progression remain largely unknown. Here, we first proposed that interface\u2010derived nanocrystal fragmentation and ectopic deposition subjected to mechanical overloading may be a potential initiator for OA progression. Ectopic deposition of nanocrystals results in mechanical stiffness of osteochondral interface extracellular matrix (ECM), which subsequently upregulates fibronectin and vitronectin expression from hypertrophic chondrocytes. Hyper\u2010mineralized vesicles, secreted by hypertrophic chondrocytes, facilitates the ECM bottom\u2010up mineralization and top\u2010down degeneration. Furthermore, mechanical overloading removal can block the ECM mineralization and degradation, and effectively reverse the OA pathology. The present work advances our comprehension of the underlying mechanisms of mechanical overloading induced OA progression and offers a foundation for potential OA therapeutic strategies.<\/jats:p>","DOI":"10.1002\/advs.202516893","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:59:41Z","timestamp":1769493581000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanical Overloading\u2010Induced Nanomineral Crystal Perturbation from the Osteochondral Interface: A Potential Initiator of Osteoarthritis"],"prefix":"10.1002","volume":"13","author":[{"given":"Nan","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases and National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu Sichuan P. R. 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