RT Journal Article SR Electronic T1 Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development JF Science Translational Medicine FD American Association for the Advancement of Science SP eaar6659 DO 10.1126/scitranslmed.aar6659 VO 11 IS 486 A1 Kang, Donghyun A1 Shin, Jungkwon A1 Cho, Yongsik A1 Kim, Hyeon-Seop A1 Gu, Young-Ran A1 Kim, Haedong A1 You, Kwon Tae A1 Chang, Moon Jong A1 Chang, Chong Bum A1 Kang, Seung-Baik A1 Kim, Jong-Seo A1 Kim, V. Narry A1 Kim, Jin-Hong YR 2019 UL http://stm.sciencemag.org/content/11/486/eaar6659.abstract AB Oxidative stress increases with aging and contributes to osteoarthritis (OA), a form of degenerative joint disease affecting cartilage and bone. Kang et al. investigated the role of cartilage cell (chondrocyte) senescence in OA. Oxidative stress induced DNA damage and senescence in chondrocytes. miR-204 was up-regulated in senescent chondrocytes and in aged and osteoarthritic human cartilage. Mice treated with miR-204 exhibited accelerated cartilage degeneration and maladaptive changes in extracellular matrix content, particularly a reduction in proteoglycan synthesis. Treatment with anti–miR-204 rescued cartilage catabolism in a posttraumatic OA mouse model and ex vivo human OA cartilage explants. This study identifies a pathway important for cartilage matrix homeostasis.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.