We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development.
- Authors
Kang, Donghyun; Shin, Jungkwon; Cho, Yongsik; Kim, Hyeon-Seop; Gu, Young-Ran; Kim, Haedong; You, Kwon Tae; Kim, Jong-Seo; Kim, V. Narry; Kim, Jin-Hong; Chang, Moon Jong; Chang, Chong Bum; Kang, Seung-Baik
- Abstract
Senescence-induced miR-204 alters the proteoglycan biosynthesis pathway and disrupts matrix homeostasis in osteoarthritic cartilage. Stress, senescence, and joint health: 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.
- Subjects
MICRORNA; CARTILAGE cells; CELLULAR aging; OSTEOARTHRITIS; PROTEOGLYCANS; OXIDATIVE stress; MAMMAL physiology
- Publication
Science Translational Medicine, 2019, Vol 11, Issue 486, pN.PAG
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aar6659