In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 11, No. 486 ( 2019-04-03)
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aar6659
Sprache:
Englisch
Verlag:
American Association for the Advancement of Science (AAAS)
Publikationsdatum:
2019