Targeting miR-18a sensitizes chondrocytes to anticytokine therapy to prevent osteoarthritis progression

Abstract

Inflammation participates in the development of OA and targeting inflammatory signaling pathways is a potential strategy for OA treatment. IL-1β is one of the most important inflammatory factors to trigger the activation of NF-κB signaling and accelerate OA progression, whereas OA patients could hardly benefit from inhibiting IL-1β in clinic, suggesting the importance to further explore the details of OA inflammation. We here showed that expression of miR-18a in chondrocytes was specifically induced in response to IL-1β in vitro as well as in rat model of OA during which NF-κB signaling was involved, and that nuclear-translocated p65 directly upregulated miR-18a expression at transcriptional level. Further, increased miR-18a mediated hypertrophy of chondrocytes, resulting in OA degeneration, by targeting TGFβ1, SMAD2, and SMAD3 and subsequently leading to repression of TGF-β signaling. And the level of serum miR-18a was positively correlated to severity of OA. Interestingly, other than IL-1β, pro-inflammation cytokines involving TNFα could also remarkably upregulate miR-18a via activating NF-κB signaling and subsequently induce chondrocytes hypertrophy, suggesting a pivotal central role of miR-18a in inflammatory OA progression. Thus, our study revealed a novel convergence of NF-κB and TGF-β signaling mediated by miR-18a, and a novel mechanism underlying inflammation-regulated OA dependent of NF-κB/miR-18a/TGF-β axis. Notably, in vivo assay showed that targeting miR-18a sensitized OA chondrocytes to IL-1β inhibitor as targeting IL-1β and miR-18a simultaneously had much stronger inhibitory effects on OA progression than suppressing IL-1β alone. Therefore, the diagnostic and therapeutic potentials of miR-18a for OA were also revealed.

Circulating microRNA alternations in primary hyperuricemia and gout

“…The expression of miR-18a is induced by IL-1β and accelerates the progression of osteoarthritis [ 19 ]. IL-1β is a pivotal cytokine in the inflammatory gout cascade; our results are consistent when we consider differences between groups where patients with hyperuricemia and gout had significantly higher levels of miR-18a; however, we did not find any difference for gout attack patients or a direct correlation between IL-1β and miR-18a levels.…”

Epigenetic therapy targeting bone marrow mesenchymal stem cells for age-related bone diseases

“…Studies have shown that miRNA is differently expressed in the cartilage of OA patients compared with the normal cartilage. Some miRNAs (e.g., miR-9, miR-18a, miR-22, miR-60) are up-regulated, [ 141 – 144 ], while others (e.g., miR-27, miR-140, miR-146, 149-5p, miR-199a, miR-miR-602, miR-608) are down-regulated [ 145 – 150 ]. The changes influence various target genes and numerous physiological mechanisms, including lipid metabolism, matrix degradation, inflammation, and chondrocytes differentiation.…”

Therapeutic effects of bone marrow mesenchymal stem cells‐derived exosomes on osteoarthritis

“…IL‐1β plays a key role in the occurrence and development of OA, which was seemed to be associated with cartilage destruction. 32 It is one of the most significant mediators of cartilage degeneration and joint inflammation. 33 IL‐1β can stimulate chondrocytes to induce the expression of MMPs, ADAMTSs and other catabolic enzymes.…”

“…These results demonstrated that MSC-Exo treatment was expected to replace MSC administration and plays a cartilage-protective role in the in vivo OA model.Furthermore, we constructed an in vitro OA model by culturing chondrocytes in IL-1β-contained medium to mimic inflammation environment in arthritis. IL-1β plays a key role in the occurrence and development of OA, which was seemed to be associated with cartilage destruction 32. It is one of the most significant mediators of cartilage degeneration and joint inflammation 33.…”