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

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 and Jin-Hong Kim (jinhkim@snu.ac.kr)
Additional contact information
Donghyun Kang: Seoul National University
Jeeyeon Lee: Seoul National University
Geunho Yook: Seoul National University
Sehan Jeong: Seoul National University
Jungkwon Shin: Seoul National University
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
Yong-ho Lee: Yonsei University
Jin Won Cho: Yonsei University
Eugene C. Yi: Seoul National University
Chanhee Kang: Seoul National University
Jin-Hong Kim: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55085-1

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