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Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway
  1. Kai Li1,2,
  2. Yue Zhang2,
  3. Yuwei Zhang2,
  4. Wenqing Jiang2,
  5. Junhui Shen2,
  6. Song Xu3,
  7. Daozhang Cai1,
  8. Jie Shen1,
  9. Bin Huang1,
  10. Mangmang Li2,
  11. Qiancheng Song2,
  12. Yu Jiang4,
  13. Anling Liu2,
  14. Xiaochun Bai1,2
  1. 1 Academy of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
  2. 2 State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
  3. 3 Department of Orthopedics and Arthroplasty, Nanfang Hospital, Southern Medical University, Guangzhou, China
  4. 4 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Xiaochun Bai, Academy of Orthopedics, The Third Affiliated Hospital of Southern Medical University; State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; baixc15{at}smu.edu.cn

Abstract

Objectives To investigate the role of tyrosine kinase Fyn in the development of osteoarthritis (OA) and the underlying mechanisms, and to define whether targeting Fyn could prevent OA in mice.

Methods Cartilage samples from normal and aged mice were analysed with proteome-wide screening. Fyn expression was examined with immunofluorescence in human and age-dependent or experimental mouse OA cartilage samples. Experimental OA in Fyn-knockout mice was induced by destabilisation of the medial meniscus. Primary cultured mouse chondrocytes were treated with proinflammatory cytokine interleukin-1β. The inhibitor of Src kinase family, AZD0530 (saracatinib), and inhibitor of Fyn, PP1, were used to treat experimental OA in mice.

Results Fyn expression was markedly upregulated in human OA cartilage and in cartilage from aged mice and those with post-traumatic OA. Fyn accumulates in articular chondrocytes and interacts directly with and phosphorylates β-catenin at Tyr142, which stabilises β-catenin and promotes its nuclear translocation. The deletion of Fyn effectively delayed the development of post-traumatic and age-dependent OA in mice. Fyn inhibitors AZD0530 and PP1 significantly attenuated OA progression by blocking the β-catenin pathway and reducing the levels of extracellular matrix catabolic enzymes in the articular cartilage.

Conclusions Fyn accumulates and activates β-catenin signalling in chondrocytes, accelerating the degradation of the articular cartilage and OA development. Targeting Fyn is a novel and potentially therapeutic approach to the treatment of OA.

  • chondrocytes
  • osteoarthritis
  • knee osteoarthritis

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors KL: study design, data acquisition, data analysis, wrote the manuscript, DMM experiments. YueZ, YuwZ, WJ and JS: data analysis, discussion of results, confocal imaging and analysis. SX, QS and DC: data acquisition, histochemistry and western blotting analysis. BH, AL and ML: data acquisition. JS and YJ: statistical analyses. XB: study design, manuscript correction.

  • Funding This work was supported by grants from the National Natural Science Foundation of China (nos. 81625015, 81530070, 31529002, 81772406).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval All animal experiments were approved by the Southern Medical University Animal Care and Use Committee (Guangzhou, China).

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

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