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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-1? is one of the most important inflammatory factors to trigger the activation of NF-?B signaling and accelerate OA progression, whereas OA patients could hardly benefit from inhibiting IL-1? 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-1? in vitro as well as in rat model of OA during which NF-?B 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 TGF?1, SMAD2, and SMAD3 and subsequently leading to repression of TGF-? signaling. And the level of serum miR-18a was positively correlated to severity of OA. Interestingly, other than IL-1?, pro-inflammation cytokines involving TNF? could also remarkably upregulate miR-18a via activating NF-?B 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-?B and TGF-? signaling mediated by miR-18a, and a novel mechanism underlying inflammation-regulated OA dependent of NF-?B/miR-18a/TGF-? axis. Notably, in vivo assay showed that targeting miR-18a sensitized OA chondrocytes to IL-1? inhibitor as targeting IL-1? and miR-18a simultaneously had much stronger inhibitory effects on OA progression than suppressing IL-1? alone. Therefore, the diagnostic and therapeutic potentials of miR-18a for OA were also revealed.

SUBMITTER: Lian C

PROVIDER: S-EPMC7609664 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Lian Chengjie C Tao Tianyu T Su Peiqiang P Liao Zhiheng Z Wang Xudong X Lei Yiting Y Zhao Pei P Liu Lei L

Cell death & disease 20201103 11

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 ind ...[more]

PMID: 33144571

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Project description:Accumulating observations in humans and animals indicate that inflammation plays a key role in atherosclerosis development and subsequent complications. Moreover, the use of loss- or gain-of-function genetically modified, atherosclerosis-prone mice has provided strong experimental evidence for a causal role of innate and adaptive immunity in atherosclerosis and has revealed the pathogenic activity of proinflammatory cytokines, including TNF (tumor necrosis factor)-?, IL (interleukin)-1?, IL-6, and IL-18, and the atheroprotective effect of anti-inflammatory cytokines, including IL-10 and TGF-?. For the past 15 years, treatments using monoclonal antibodies specifically targeting cytokines, commonly referred as biological therapies, have transformed the treatment of chronic inflammatory diseases, such as rheumatoid arthritis or psoriasis, both conditions associated with increased cardiovascular risk. Analyzing the impact of anticytokine therapies on the cardiovascular outcomes of patients with chronic inflammatory diseases provides insight into the clinical relevance of experimental data on the role of inflammation in atherothrombotic cardiovascular diseases. CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) provided the first evidence that targeting inflammation in humans with atherosclerosis could improve clinical outcomes. Treatment with the anti-IL-1? antibody canakinumab significantly reduced recurrent cardiovascular events in individuals with stable coronary artery disease well-treated with standard-of-care measures. Other clinical studies support the protective effects of treatment with anti-TNF-? and anti-IL-6 receptor monoclonal antibodies on cardiovascular risk. Blockade of the IL-23/IL-17 axis, however, warrants caution as a cardiovascular intervention. Targeting this pathway has improved psoriasis but may augment cardiovascular risk in certain patients. Thus, careful consideration of the cardiovascular risk profile may influence the choice of the most appropriate treatment for patients with chronic inflammatory diseases.Visual Overview: An online visual overview is available for this article.

Dataset Information

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

Publications

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

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