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Nat. Commun., 04 February 2025 | https://doi.org/10.1038/s41467-024-55085-1
Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation
Donghyun Kang1,2,12, Jeeyeon Lee1,2,12, Geunho Yook1,2, Sehan Jeong1,2, Jungkwon Shin1,2, Mi-Sung Kim1, Yi-Jun Kim3, Hyeryeon Jung4, Jinsung Ahn4, Tae Woo Kim5, Moon Jong Chang5, Chong Bum Chang6, Seung-Baik Kang5, Won Ho Yang7,8, Yong-ho Lee8,9, Jin Won Cho7,8, Eugene C. Yi4,8, Chanhee Kang1 & Jin-Hong Kim1,2,8,10,11
1Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
2Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea.
3Department of Environmental Medicine, College of Medicine, Ewha Womans University, Seoul 07985, South Korea.
4Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul 03080, South Korea.
5Department of Orthopaedic Surgery, Seoul National University Boramae Hospital, Seoul 07061, South Korea.
6Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea.
7Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
8Glycosylation Network Research Center, Yonsei University, Seoul 03722, South Korea.
9Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
10Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang 25354, South Korea.
11Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea.
12These authors contributed equally: Donghyun Kang, Jeeyeon Lee.
Corresponding author
Correspondence to Jin-Hong Kim.
1Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
2Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea.
3Department of Environmental Medicine, College of Medicine, Ewha Womans University, Seoul 07985, South Korea.
4Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul 03080, South Korea.
5Department of Orthopaedic Surgery, Seoul National University Boramae Hospital, Seoul 07061, South Korea.
6Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea.
7Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
8Glycosylation Network Research Center, Yonsei University, Seoul 03722, South Korea.
9Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea.
10Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang 25354, South Korea.
11Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea.
12These authors contributed equally: Donghyun Kang, Jeeyeon Lee.
Corresponding author
Correspondence to Jin-Hong Kim.
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-07)
- 국내 연구진
- 생명과학 > 노화/암생물학
관련 보도자료
연골의 노화와 퇴행성관절염, 단백질 당화에 원인이 있었다!
최근 국내 연구진이 당 수식화에 의한 연골 노화와 퇴행성관절염 가속화 현상을 새롭게 밝혀내 퇴행성관절염의 병인 기전을 이해하고 질병 치료의 표적을 발굴하는 데 중요한 발견을 했다. 서울대 생명과학부 김진홍 교수와 강동현 연구교수 등이 주도한 연구팀이 “Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation”이라는 제목의 논문을 통해 발표한 이번 연구결과는 2025년 2월 4일자로 네이처 커뮤니케이션지에 게재되었다.
- Bio통신원
- 2025. 02. 05
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