Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation
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.
Authors
- Jungkwon Shin (ORCID: https://orcid.org/0000-0003-1068-1615)
- Moon Jong Chang (ORCID: https://orcid.org/0000-0002-2352-7599)
- Donghyun Kang (ORCID: https://orcid.org/0000-0003-1966-1397)
- Hyeryeon Jung (ORCID: https://orcid.org/0000-0001-5179-8604)
- Jinsung Ahn
- Jin Won Cho (ORCID: https://orcid.org/0000-0003-4527-1755)
- Mi-Sung Kim (ORCID: https://orcid.org/0000-0003-0320-735X)
- Won Ho Yang (ORCID: https://orcid.org/0000-0001-6214-1421)
- Seok Hoo Jeong (ORCID: https://orcid.org/0000-0001-9197-1184)
- Seung‐Baik Kang (ORCID: https://orcid.org/0000-0002-1184-4482)
- Jeeyeon Lee (ORCID: https://orcid.org/0000-0001-6489-1832)
- Yi‐Jun Kim (ORCID: https://orcid.org/0000-0002-1763-4267)
- Eugene C. Yi (ORCID: https://orcid.org/0000-0002-0615-7397)
- Chanhee Kang (ORCID: https://orcid.org/0000-0003-4350-5706)
- Chong Bum Chang (ORCID: https://orcid.org/0000-0002-8597-1054)
- Geunho Yook (ORCID: https://orcid.org/0009-0007-7676-6917)
- Tae‐Woo Kim (ORCID: https://orcid.org/0000-0002-5180-0978)
- Yong‐ho Lee (ORCID: https://orcid.org/0000-0002-6219-4942)
- Jin‐Hong Kim (ORCID: https://orcid.org/0000-0002-6480-1929)
Institutions
- Seoul National University of Science and Technology (KR)
- Ewha Womans University (KR)
- Seoul National University (KR)
- Yonsei University (KR)
- Seoul National University Bundang Hospital (KR)
- SNUH SMG-SNU Boramae Medical Center (KR)
- Institute for Basic Science (KR)
- National University College (PR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s41467-024-55085-1
- Citations
- 20
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 15.31
Funders
- National Research Foundation
- Ministry of Science, ICT and Future Planning
- National Research Foundation of Korea
- Korea Drug Development Fund
- Institute for Basic Science
- Ministry of Science and ICT, South Korea