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  3. Mechanism of Piezo1 regulating chondrocyte mitochondrial function and promoting fracture healing through β-catenin/LARS2 signaling pathway

Mechanism of Piezo1 regulating chondrocyte mitochondrial function and promoting fracture healing through β-catenin/LARS2 signaling pathway

  • Bone Res. 2025 Sep 24;13(1):79. doi: 10.1038/s41413-025-00459-4.
Tao Zhang # 1 2 3,  Hongzhi Lv # 1 2 3,  Siming Jia # 1 2 3,  Lijun Wang 4 5,  Weijian Liu 6,  Kai Ding 1 2 3,  Xiaofeng Du 1 2 3,  Guangzhao Hou 1 2 3,  Zhiyong Hou 1 2 3 7,  Yingze Zhang 1 2 3 7,  Weiguo Zou 8 9,  Wei Chen 10 11 12 13,  Yanbin Zhu 14 15 16 17
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China.
  • 2 Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China.
  • 3 NHC Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, Hebei, China.
  • 4 Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Haikou, Hainan, China. wanglijun2014@sibcb.ac.cn.
  • 5 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, China. wanglijun2014@sibcb.ac.cn.
  • 6 Department of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 7 Engineering Research Center of Orthopedic MinimallyInvasive Intelligent Equipment, Ministry of Education, Shijiazhuang, Hebei, China.
  • 8 Hainan Institute of Regenerative Orthopedics and Sports Medicine, Hainan Academy of Medical Sciences and School of Basic Medicine, Hainan Medical University, Haikou, Hainan, China.
  • 9 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, China.
  • 10 Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China. surgeonchenwei@126.com.
  • 11 Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China. surgeonchenwei@126.com.
  • 12 NHC Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, Hebei, China. surgeonchenwei@126.com.
  • 13 Engineering Research Center of Orthopedic MinimallyInvasive Intelligent Equipment, Ministry of Education, Shijiazhuang, Hebei, China. surgeonchenwei@126.com.
  • 14 Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, China. 38600312@hebmu.edu.cn.
  • 15 Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China. 38600312@hebmu.edu.cn.
  • 16 NHC Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, Hebei, China. 38600312@hebmu.edu.cn.
  • 17 Engineering Research Center of Orthopedic MinimallyInvasive Intelligent Equipment, Ministry of Education, Shijiazhuang, Hebei, China. 38600312@hebmu.edu.cn.
  • # Contributed equally.
PMID: 40993116 DOI: 10.1038/s41413-025-00459-4
Abstract

Piezo1, a key mechanosensor in bone homeostasis, plays a crucial role in fracture healing. However, the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood. This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification. Using lineage tracing, we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification, which was impaired by chondrocyte-specific Piezo1 knockout. Piezo1 deficiency disrupted mitochondrial bioenergetics, characterized by diminished membrane potential, reduced adenosine triphosphate (ATP) synthesis, suppressed oxygen consumption rates (basal and maximal respiration), and elevated mitochondrial superoxide generation, thereby impairing endochondral ossification during fracture healing. Single-cell RNA Sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout. Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers (MFN1, MFN2, OPA1, DRP1) and restored mitochondrial functional homeostasis. This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers (Col1, ALP, OCN, OPN, RUNX2), thereby enhancing fracture repair. Protein interaction analyses confirmed direct binding between β-catenin and Lars2. Mechanistically, Piezo1 governs Lars2 expression via β-catenin signaling. Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through the β-catenin/Lars2 axis, offering novel insights and therapeutic avenues for fracture treatment.

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