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Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7
  1. Haiyan Zhang1,2,
  2. Yan Shao1,2,
  3. Zihao Yao1,2,
  4. Liangliang Liu1,2,
  5. Hongbo Zhang1,2,
  6. Jianbin Yin1,2,
  7. Haoyu Xie1,2,
  8. Kai Li1,2,
  9. Pinglin Lai1,2,
  10. Hua Zeng1,2,
  11. Guozhi Xiao3,
  12. Chun Zeng1,2,
  13. Daozhang Cai1,2,
  14. Xiaochun Bai1,2
  1. 1 Department of Orthopedics, Academy of Orthopedics·Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
  2. 2 Department of Joint Surgery, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third School of Clinical Medicine, Southern Medical University, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
  3. 3 Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China
  1. Correspondence to Dr Xiaochun Bai, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; baixc15{at}smu.edu.cn; Professor Daozhang Cai, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; cdz{at}smu.edu.cn; Dr Chun Zeng, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; zengdavid{at}126.com

Abstract

Objectives To investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression.

Methods F-box and WD repeat domain containing 7 (FBXW7) ubiquitin ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA sequencing was performed in articular cartilage from Fbxw7 knockout and control mice.

Results Mechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degeneration

Conclusions FBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.

  • osteoarthritis
  • chondrocytes
  • therapeutics

Data availability statement

Data are available in a public, open access repository. Not applicable.

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Data availability statement

Data are available in a public, open access repository. Not applicable.

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Footnotes

  • Handling editor Josef S Smolen

  • HZ, YS and ZY contributed equally.

  • Contributors HyZ and XB conceived the ideas for experimental designs, analysed data and wrote the manuscript. HyZ and YS conducted the majority of the experiments and helped with manuscript preparation. ZY conducted the majority of the experiments and analysed data during the revision of the article. CZ, HbZ and LL performed immunohistochemistry and immunofluorescence and confocal imaging. HbZ and KL conducted cell cultures and western blot experiments. JY and ZY collected human tissue samples. CZ, XB and DC developed the concept, supervised the project and conceived the experiments. All authors approved the final version of the manuscript. XB accepted full responsibility for the finished work, had access to the data and controlled the decision to publish.

  • Funding This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81974341, 81991510 and 81991511) and the Natural Science Foundation of Guangdong Province (2020A1515011062).

  • Competing interests None declared.

  • 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.

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