- Authors: Kang D, Shin J, Cho Y, Kim HS, Gu YR, Kim H, You KT, Chang M, Chang CB, Kang SB, Kim JS, Kim VN, Kim JH.. et al.
- Year: 2019
- Journal: Sci Transl Med Vol. 11, Issue 486, eaar6659
- Applications: in vivo / miRNA / in vivo-jetPEI
miRCtrl or miR-204 was intra-articularly delivered to mouse knee joints using an in vivo transfection reagent, in vivo-jetPEI (0.4 mg/kg of miRNA; once every 2 weeks for 10 weeks).
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.