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Spondyloarthritis
Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis
  1. Siwen Chen1,2,
  2. Zihao Li1,2,
  3. Dongying Chen3,
  4. Haowen Cui1,2,
  5. Jianru Wang1,2,
  6. Zemin Li1,2,
  7. Xiang Li1,2,
  8. Zhaomin Zheng1,2,
  9. Zhongping Zhan3,
  10. Hui Liu1,2
  1. 1 Department of Spine Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  2. 2 Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, Guangdong, China
  3. 3 Deparment of Rheumatology and Immunology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  1. Correspondence to Dr Hui Liu, Department of Spine Surgery, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, 510080, China; liuhui58{at}mail.sysu.edu.cn

Abstract

Objective The aim of this study was to identify the role of Piezo1-mediated mechanotransduction in entheseal pathological new bone formation and to explore the underlying molecular mechanism.

Methods Spinal ligament tissues were collected from 14 patients with ankylosing spondylitis (AS) and 14 non-AS controls and bulk RNA sequencing was conducted. Collagen antibody-induced arthritis models were established to observe pathological new bone formation. Pharmacological inhibition and genetic ablation of Piezo1 was performed in animal models to identify the essential role of Piezo1. Entheseal osteo-chondral lineage cells were collected and in vitro cell culture system was established to study the role and underlying mechanism of Piezo1 in regulation of chondrogenesis, osteogenesis and its own expression.

Results Piezo1 was aberrantly upregulated in ligaments and entheseal tissues from patients with AS and animal models. Pharmaceutical and genetic inhibition of Piezo1 attenuated while activation of Piezo1 promoted pathological new bone formation. Mechanistically, activation of CaMKII (Calcium/calmodulin dependent protein kinase II) signalling was found essential for Piezo1-mediated mechanotransduction. In addition, Piezo1 was upregulated by AS-associated inflammatory cytokines.

Conclusion Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation through CaMKII signalling in AS.

  • Autoimmune Diseases
  • Arthritis, Experimental
  • Spondylitis, Ankylosing

Data availability statement

Data are available on reasonable request. The data that support the findings in this study are available from the corresponding author on request.

http://dx.doi.org/10.1136/ard-2022-223428

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    Data availability statement

    Data are available on reasonable request. The data that support the findings in this study are available from the corresponding author on request.

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    Footnotes

    • Handling editor Josef S Smolen

    • SC, ZL and DC contributed equally.

    • Contributors SC, ZL and DC contributed equally to this work. HL conceived the ideas for experimental designs and is responsible for the overall content as the guarantor. SC, ZL and DC conducted the majority of the experiments, analysed data, and prepared the manuscript. SC, JW and ZL conducted sample collection and performed statistical analysis. XL, HC, JW, ZhaZ and ZhoZ provided critical suggestions and instructions for the project and helped compose the manuscript. SC and DC provided μCT analysis. SC, DC and ZL conducted the most animal experiments and performed analysis. HL developed the concept, supervised the project and conducted data analysis.

    • Funding The work was supported by National Natural Science Foundation of China (Grant no 81972039; 81772307), Department of Science and Technology of Guangdong Province (Grant no 2021B1515020080; 2017A050501016), Special Support Plan for High-Level Talent of Guangdong Province, China (Grant no 2016TQ03R667) and KELIN New Talent Project of The First Affiliated Hospital, Sun Yat-sen University (Grant no Y12001).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.