ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2022; 18(10):3961-3980. doi:10.7150/ijbs.71390 This issue Cite
Research Paper
Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing
1. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
2. Department of Orthopedics, The Eighth People's Hospital, Jiangsu University, Shanghai 200235, China.
3. Department of Orthopedics, Xuhui Branch of The Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.
4. Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou 450003, Henan, China.
5. Department of Orthopedics, The Third Hospital of Hebei Medical University, Shi Jiazhuang 050051, Hebei, China.
6. NHC Key Laboratory of Intelligent Orthopedic Equipment (The Third Hospital of Hebei Medical University), Shi Jiazhuang 050051, Hebei, China.
*These authors contributed equally to the work.
Abstract
The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1 in fracture healing is not yet well characterized. In this study, we first delineated that Piezo1 is highly expressed in periosteal stem cells (PSCs) and their derived osteoblastic lineage cells and chondrocytes. Furthermore, downregulation of Piezo1 in callus leads to impaired fracture healing, while activation by its specific agonist promotes fracture healing through stimulation of PSC-modulated chondrogenesis and osteogenesis, along with accelerated cartilage-to-bone transformation. Interestingly, vascular endothelial growth factor A is upregulated after Yoda1 treatment of PSCs, indicating an indirect role of Piezo1 in angiogenesis. Mechanistically, activation of Piezo1 promotes expression of Yes-associated protein (YAP) and its nuclear localization in PSCs, which in turn increases the expression and nuclear localization of β-catenin. In detail, YAP directly interacts with β-catenin in the nucleus and forms a transcriptional YAP/β-catenin complex, which upregulates osteogenic, chondrogenic and angiogenic factors. Lastly, Yoda1 treatment significantly improves fracture healing in a delayed union mouse model generated by tail suspension. These findings indicate that Piezo1 is a potential therapeutic target for fracture delayed union or nonunion.
Keywords: Piezo1, Mechanosensor, PSCs, Fracture healing, YAP
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