Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation
Donghyun Kang, Jeeyeon Lee, Geunho Yook, Seok Hoo 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
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. Here, the authors show that reduced transport of UDP-GlcNAc to the endoplasmic reticulum and Golgi leads to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. This, in turn, stabilizes the transcription factor GATA4, promoting the senescence-associated secretory phenotype and exacerbating osteoarthritis.