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.