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Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis

Author

Listed:
  • Fenli Shao

    (Nanjing University)

  • Qianqian Liu

    (Nanjing University)

  • Yuyu Zhu

    (Nanjing University
    Nanjing University of Chinese Medicine)

  • Zhidan Fan

    (Children’s Hospital of Nanjing Medical University)

  • Wenjun Chen

    (Affiliated Hospital of Nanjing University of Chinese Medicine)

  • Shijia Liu

    (Affiliated Hospital of Nanjing University of Chinese Medicine)

  • Xiaohui Li

    (Children’s Hospital of Nanjing Medical University)

  • Wenjie Guo

    (Nanjing University)

  • Gen-Sheng Feng

    (University of California San Diego)

  • Haiguo Yu

    (Children’s Hospital of Nanjing Medical University)

  • Qiang Xu

    (Nanjing University
    Xuzhou Medical University)

  • Yang Sun

    (Nanjing University
    Xuzhou Medical University
    Nanjing University)

Abstract

Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11f/f mice, which present the pathophysiological features of AS. A population of CD4-Cre-expressing proliferating chondrocytes was SHP2 deficient, which could differentiate into pre-hypertrophic and hypertrophic chondrocytes. Functionally, SHP2 deficiency in chondrocytes impeded the fusion of epiphyseal plate and promoted chondrogenesis in joint cavity and enthesis. Mechanistically, aberrant chondrocytes promoted ectopic new bone formation through BMP6/pSmad1/5 signaling. It is worth emphasizing that such pathological thickness of growth plates was evident in adolescent humans with enthesitis-related arthritis, which could progress to AS in adulthood. Targeting dysfunctional chondrogenesis with Smo inhibitor sonidegib significantly alleviated the AS-like bone disease in mice. These findings suggest that blockade of chondrogenesis by sonidegib would be a drug repurposing strategy for AS treatment.

Suggested Citation

  • Fenli Shao & Qianqian Liu & Yuyu Zhu & Zhidan Fan & Wenjun Chen & Shijia Liu & Xiaohui Li & Wenjie Guo & Gen-Sheng Feng & Haiguo Yu & Qiang Xu & Yang Sun, 2021. "Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26750-6
    DOI: 10.1038/s41467-021-26750-6
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    References listed on IDEAS

    as
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    3. Kimberly L. Cooper & Seungeun Oh & Yongjin Sung & Ramachandra R. Dasari & Marc W. Kirschner & Clifford J. Tabin, 2013. "Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions," Nature, Nature, vol. 495(7441), pages 375-378, March.
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