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<p>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 <i>Gata4</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月4日

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  • 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,
  • Won Ho Yang,
  • Yong-ho Lee,
  • Jin Won Cho,
  • Eugene C. Yi,
  • Chanhee Kang,
  • Jin-Hong Kim

摘要

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.