한빛사 논문
Donghyun Kang1,2,*, Jungkwon Shin1,2,*, Yongsik Cho1,2, Hyeon-Seop Kim1,2, Young-Ran Gu1,2, Haedong Kim1,2, Kwon Tae You1,2, Moon Jong Chang3, Chong Bum Chang3, Seung-Baik Kang3, Jong-Seo Kim1,2, V. Narry Kim1,2 and Jin-Hong Kim1,2,4,†
1Center for RNA Research, Institute for Basic Science, 08826 Seoul, South Korea.
2Department of Biological Sciences, College of Natural Sciences, Seoul National University, 08826 Seoul, South Korea.
3Department of Orthopedic Surgery, Seoul National University College of Medicine, Boramae Hospital, 07061 Seoul, South Korea.
4Interdisciplinary Program in Bioinformatics, Seoul National University, 08826 Seoul, South Korea.
†Corresponding author.
* These authors contributed equally to this work.
Abstract
A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development. Here, we identify miR-204 as a markedly up-regulated microRNA in OA cartilage. miR-204 is induced by transcription factors GATA4 and NF-κB in response to senescence signals. Up-regulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas miR-204 inhibition ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilage. Collectively, we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.
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