Role of miR-146a in human chondrocyte apoptosis in response to mechanical pressure injury in vitro

Jin, Lei; Zhao, Jian; Jing, Wensen; Yan, Shuhua; Wang, Xinxin; Xiao, Chun; Ma, Baoan

doi:10.3892/ijmm.2014.1808

Cited by 94 publications

(101 citation statements)

References 72 publications

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“…MiR146a was over-expressed in the chondrocytes model of experimentally induced human mechanical injury, accompanied by the up-regulation of VEGF and the down-regulation of Smad4 in vitro. miR-146a is involved in human chondrocytes apoptosis in response to mechanical injury and may contribute to the mechanical injury of chondrocytes as well as to OA pathogenesis by promoting VEGF expression and impairing the TGF-β signaling pathway through inhibiting Smad4 in cartilage [43]. Both of these studies confirmed the participation of the VEGF, Smad4 and TGF-β signaling pathway during the miR-146a-mediated OA pathology and discovered that Smad4 is the target of miR-146a in this process.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

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“…miR-146a was found to target and downregulate Smad4 , which subsequently induced VEGF expression and increased articular chondrocytes apoptosis. Another in vitro study using human articular chondrocytes has also shown that miR-146a is induced in chondrocytes by pressure-mediated mechanical stress [57]. This was accompanied by Smad4 downregulation, VEGF upregulation, and increased chondrocyte apoptosis.…”

Section: Role Of Microrna In Articular Cartilage Homeostasis and Ostementioning

confidence: 99%

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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“…6 The emerging role of miRNAs in OA is evident from studies comparing miRNA expression in both OA and normal articular tissues. miRNAs, including miR-140, 7,8 miR-320c, 9 miR-125b, 10 miR-27b, 11 miR-194, 12 miR-199a*, 13 miR-34a, 14 and miR-146a, 15 are implicated in various aspects of OA pathology, including regulating proteolytic enzymes, chondrocyte metabolism, and cartilage homeostasis and responding to the inflammatory microenvironment. Therefore, identification of the miRNAs regulatory network involved in OA is crucial for understanding its pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

et al. 2017

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MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p and delivered it intra-articularly, which revealed that antagomiR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and it consequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.

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Role of miR-146a in human chondrocyte apoptosis in response to mechanical pressure injury in vitro

Cited by 94 publications

References 72 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

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

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