Insufficient Mechanical Loading Downregulates Piezo1 in Chondrocytes and Impairs Fracture Healing Through ApoE-Induced Senescence

  • Adv Sci (Weinh). 2024 Oct 17:e2400502. doi: 10.1002/advs.202400502.
Siming Jia  1  2 ,  Weijian Liu  3 ,  Mo Zhang  2  4 ,  Lijun Wang  5  6 ,  Chuan Ren  1 ,  Chen Feng  1 ,  Tao Zhang  1 ,  Hongzhi Lv  1 ,  Zhiyong Hou  1 ,  Weiguo Zou  5  6 ,  Yingze Zhang  1 ,  Wei Tong  3 ,  Juan Wang  1 ,  Wei Chen  1
Affiliations
  • 1. Department of Orthopaedic Surgery, NHC Key Laboratory of Intelligent Orthopaedic Equipment, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, 050051, China.
  • 2. Hebei Medical University Clinical Medicine Postdoctoral Station (Hebei Medical University Third Hospital), Shijiazhuang, Hebei, 050051, China.
  • 3. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
  • 4. School of Pharmacy, Key Laboratory of Innovative Drug Development and Evaluation, Hebei Medical University, Shijiazhuang, 050017, China.
  • 5. Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Hainan, 570000, China.
  • 6. Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
PMID: 39418070 DOI: 10.1002/advs.202400502
Abstract

Insufficient mechanical loading impairs fracture healing; however, the underlying mechanisms remain unclear. 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-regulates the expression of Piezo1 in chondrocytes and leads to fracture nonunion. Single-cell 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-to-bone 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-to-bone 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.

Keywords
ApoE; Piezo1; endochondral ossification; fracture healing; mechanical loading.
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