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Increasing evidence indicates that Piezo1 plays an important role in fracture healing, although the effect of Piezo1 on the endochondral ossification of chondrocytes has been overlooked. This study reports that mechanical unloading down\u2010regulates the expression of Piezo1 in chondrocytes and leads to fracture nonunion. Single\u2010cell sequencing of calluses revealed that specific deletion of Piezo1 in chondrocytes upregulated the expression of apolipoprotein E (ApoE) in hypertrophic chondrocytes, resulting in delayed cartilage\u2010to\u2010bone transition due to enhanced chondrocyte senescence. Based on these results, an injectable and thermosensitive hydrogel is developed, which released an ApoE antagonist in situ at the fracture site. This hydrogel effectively attenuated chondrocyte senescence and, thus, promoted cartilage\u2010to\u2010bone transition as well as the fracture healing process. Overall, this data provide a new perspective on the activity of chondrocytes in fracture healing and a new direction for the treatment of fracture nonunion caused by insufficient mechanical loading.<\/jats:p>","DOI":"10.1002\/advs.202400502","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T11:31:16Z","timestamp":1729164676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Insufficient Mechanical Loading Downregulates Piezo1 in Chondrocytes and Impairs Fracture Healing Through ApoE\u2010Induced Senescence"],"prefix":"10.1002","volume":"11","author":[{"given":"Siming","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, NHC Key Laboratory of Intelligent Orthopaedic Equipment Hebei Medical University Third Hospital  Shijiazhuang Hebei 050051 China"},{"name":"Hebei Medical University Clinical Medicine Postdoctoral Station (Hebei Medical 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