OP0202 STRESS-ACTIVATED MIR-204 GOVERNS SENESCENT PHENOTYPES OF CHONDROCYTES TO PROMOTE OSTEOARTHRITIS DEVELOPMENT

Abstract

Background: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.Objectives:We sought to identify a previously unknown, senescence-associated signaling pathway in chondrocytes linked to major OA cartilage manifestations such as PG loss and cartilage degeneration.Methods:We particularly aimed to screen miRNAs whose inhibition could effectively modulate senescent phenotypes of chondrocytes to treat OA. We investigated the regulatory mechanisms of miR-204 under various stress-eliciting stimuli in primary cultured human and mouse chondrocytes. We examined the in vivo effects of miR-204 overexpression and its antagonism in surgically induced OA mouse models. DMM surgery was used to induce posttraumatic OA in 12-week-old mice. Small RNAs were delivered to mouse knee joints by intra-articular injection. Various OA manifestations including cartilage destruction, subchondral bone sclerosis, osteophyte maturity, and synovial inflammation in mice were histologically inspected.Results:We identify miR-204 as a senescence-associated microRNA (miRNA) which is markedly upregulated in OA cartilage. The upregulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of the miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas inhibition of miR-204 ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilageConclusion:we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.