Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1β signaling in osteoarthritis fibroblast-like synoviocytes

Wang, J.H.; Shih, Kao-Shang; Wu, Yiwen; Wang, A.W.; Yang, Congrong

doi:10.1016/j.joca.2013.09.008

Cited by 86 publications

(73 citation statements)

References 37 publications

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“…This result suggested a negative feedback between miR146a and inflammatory factors, considering that miR-146a was up-regulated in the RA pathology, and the administration of miR-146a may serve as a novel therapeutic target for bone destruction in RA [45]. The negative feedback of miR-146a with inflammatory factors was further confirmed in osteoarthritis fibroblast-like synoviocytes [46], osteoarthritis pain in knee joints [47], and intervertebral disc [48]. Apparently, there is still a great controversy on the role of miR-146a with two opposite conclusions, and one study reported a downregulation of miR-146 in OA cartilage, further mystifying the issue [49].…”

Section: Discussionmentioning

confidence: 65%

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

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Background/Aims: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. Methods: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. Results: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. Conclusion: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

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Section: Discussionmentioning

confidence: 65%

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

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“…This was accompanied by Smad4 downregulation, VEGF upregulation, and increased chondrocyte apoptosis. miR-146a expression is also induced by HDAC inhibitor treatment in synovial fibroblasts isolated from OA patients [58]. This study showed that HDAC inhibitor treatment increased NF-κB binding to the promoter region of the miR-146a gene.…”

Section: Role Of Microrna In Articular Cartilage Homeostasis and Ostementioning

confidence: 92%

microRNAs in Cartilage Development, Homeostasis, and Disease

Mirzamohammadi

Papaioannou

Kobayashi

2014

Curr Osteoporos Rep

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microRNAs (miRNAs) regulate gene expression mainly at the posttranscriptional level. Many different miRNAs are expressed in chondrocytes, and each individual miRNA can regulate hundreds of target genes, creating a complex gene regulatory network. Experimental evidence suggests that miRNAs play significant roles in various aspects of cartilage development, homeostasis, and pathology. The possibility that miRNAs can be novel therapeutic targets for cartilage diseases led to vigorous investigations to understand the role of individual miRNAs in skeletal tissues. Here, we summarize our current understanding of miRNAs in chondrocytes and cartilage. In the first part, we discuss roles of miRNAs in growth plate development and chondrocyte differentiation. In the second part, we put a particular focus on articular cartilage and discuss the significance of variety of findings in the context of osteoarthritis, the most common degenerative joint disease.

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“…Previously, it was shown that HDACi treatment could rapidly alter miR expression levels, either increasing or decreasing certain subsets of micro-RNA. [50][51][52][53] Future studies should include dissecting how and why HDACi differentially regulate the expression of miR subsets. Investigating whether different classes of HDACi affect miR expression similarly may lead to a better understanding of HDACi treatments and the epigenetic regulation of miRs.…”

Section: Discussionmentioning

confidence: 99%

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

2017

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microRNAs (miRs) are small noncoding RNAs that regulate/fine tune many cellular protein networks by targeting mRNAs for either degradation or translational inhibition. Dicer, a type III endoribonuclease, is a critical component in miR biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. Recent reports have demonstrated that epigenetic agents, including histone deacetylase inhibitors (HDACi), may regulate Dicer and miR expression. HDACi are a class of epigenetic agents used to treat cancer, viral infections, and inflammatory disorders. However, little is known regarding the epigenetic regulation of miR biogenesis and function. We therefore investigated whether clinically successful HDACi modulated Dicer expression and found that Panobinostat, a clinically approved HDACi, enhanced Dicer expression via posttranscriptional mechanisms. Studies using proteasome inhibitors suggested that Panobinostat regulated the proteasomal degradation of Dicer. Further studies demonstrated that Panobinostat, despite increasing Dicer protein expression, decreased Dicer activity. This suggests that Dicer protein levels do not necessarily correlate with Dicer activity and mature miR levels. Taken together, we present evidence here that Panobinostat posttranscriptionally regulates Dicer/miR biogenesis and suggest Dicer as a potential therapeutic target in cancer.

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Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1β signaling in osteoarthritis fibroblast-like synoviocytes

Cited by 86 publications

References 37 publications

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

microRNAs in Cartilage Development, Homeostasis, and Disease

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

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