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Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation

Author

Listed:
  • Donghyun Kang

    (Seoul National University
    Institute for Basic Science)

  • Jeeyeon Lee

    (Seoul National University
    Institute for Basic Science)

  • Geunho Yook

    (Seoul National University
    Institute for Basic Science)

  • Sehan Jeong

    (Seoul National University
    Institute for Basic Science)

  • Jungkwon Shin

    (Seoul National University
    Institute for Basic Science)

  • Mi-Sung Kim

    (Seoul National University)

  • Yi-Jun Kim

    (Ewha Womans University)

  • Hyeryeon Jung

    (Seoul National University)

  • Jinsung Ahn

    (Seoul National University)

  • Tae Woo Kim

    (Seoul National University Boramae Hospital)

  • Moon Jong Chang

    (Seoul National University Boramae Hospital)

  • Chong Bum Chang

    (Seoul National University Bundang Hospital)

  • Seung-Baik Kang

    (Seoul National University Boramae Hospital)

  • Won Ho Yang

    (Yonsei University
    Yonsei University)

  • Yong-ho Lee

    (Yonsei University
    Yonsei University College of Medicine)

  • Jin Won Cho

    (Yonsei University
    Yonsei University)

  • Eugene C. Yi

    (Seoul National University
    Yonsei University)

  • Chanhee Kang

    (Seoul National University)

  • Jin-Hong Kim

    (Seoul National University
    Institute for Basic Science
    Yonsei University
    Seoul National University)

Abstract

UDP-GlcNAc serves as a building block for glycosaminoglycan (GAG) chains in cartilage proteoglycans and simultaneously acts as a substrate for O-GlcNAcylation. Here, we show that transporters for UDP-GlcNAc to the endoplasmic reticulum (ER) and Golgi are significantly downregulated in osteoarthritic cartilage, leading to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. Mechanistically, upregulated O-GlcNAcylation governs the senescence-associated secretory phenotype (SASP) by stabilizing GATA4 via O-GlcNAcylation at S406, which compromises its degradation by p62-mediated selective autophagy. Elevated O-GlcNAcylation in the superficial layer of osteoarthritic cartilage coincides with increased GATA4 levels. The topical deletion of Gata4 in this cartilage layer ameliorates post-traumatic osteoarthritis (OA) in mice while inhibiting O-GlcNAc transferase mitigates OA by decreasing GATA4 levels. Excessive glucosamine-induced O-GlcNAcylation stabilizes GATA4 in chondrocytes and exacerbates post-traumatic OA in mice. Our findings elucidate the role of UDP-GlcNAc compartmentalization in regulating secretory pathways associated with chronic joint inflammation, providing a senostatic strategy for the treatment of OA.

Suggested Citation

  • Donghyun Kang & Jeeyeon Lee & Geunho Yook & Sehan Jeong & Jungkwon Shin & Mi-Sung Kim & Yi-Jun Kim & Hyeryeon Jung & Jinsung Ahn & Tae Woo Kim & Moon Jong Chang & Chong Bum Chang & Seung-Baik Kang & W, 2025. "Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55085-1
    DOI: 10.1038/s41467-024-55085-1
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    References listed on IDEAS

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    1. Sandra Weimer & Josephine Priebs & Doreen Kuhlow & Marco Groth & Steffen Priebe & Johannes Mansfeld & Troy L. Merry & Sébastien Dubuis & Beate Laube & Andreas F. Pfeiffer & Tim J. Schulz & Reinhard Gu, 2014. "D-Glucosamine supplementation extends life span of nematodes and of ageing mice," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    2. Sukyeong Kim & Sangbin Han & Yeongjae Kim & Hyeon-Seop Kim & Young-Ran Gu & Donghyun Kang & Yongsik Cho & Hyeonkyeong Kim & Jeeyeon Lee & Yeyoung Seo & Moon Jong Chang & Chong Bum Chang & Seung-Baik K, 2019. "Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    3. Xiaoyong Yang & Pat P. Ongusaha & Philip D. Miles & Joyce C. Havstad & Fengxue Zhang & W. Venus So & Jeffrey E. Kudlow & Robert H. Michell & Jerrold M. Olefsky & Seth J. Field & Ronald M. Evans, 2008. "Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance," Nature, Nature, vol. 451(7181), pages 964-969, February.
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