miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway

Li, H.; Li, T.; Fan, Junfen; Fan, Linyuan; Wang, S.; Weng, Xisheng; Han, Qihang; Zhao, Robert Chunhua

doi:10.1038/cdd.2015.99

Cited by 116 publications

(78 citation statements)

References 58 publications

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“…Among those identified were miR-130a and miR-15B, which are known to regulate Wnt signalling [40,41] and are identified as biomarker of atherosclerosis obliterans [42]. miR-154 was found to be a biomarker for CAD [43]; and miR216A has roles in osteogenesis and cholesterol efflux via PI3K/AKT pathway [44,45]. Some of the microRNAs identified are also implicated in the pro-fibrotic TGF-β signalling pathway and found to be involved in fibrosis by targeting extracellular matrix structural proteins and enzymes involved in cellular remodeling.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Yu¹,

Kapur²,

Hamid³

et al. 2018

J Pharmacogenomics Pharmacoproteom

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Aortic valve stenosis is one of the most common valve diseases in the world for which there is currently no pharmacological treatment to prevent or halt disease progression. Recent genetic research has demonstrated a causal association between elevated blood levels of lipoprotein (a) (Lp (a)) and aortic valve calcification, however, the mechanisms by which Lp (a) contributes to aortic valve calcification and stenosis, is unknown. In the present study, we aimed at determining Lp (a)-induced changes in human aortic valve interstitial cells using an integrated bioinformatics approach. The Lp (a)-induced cellular pathways were analysed using microarray gene expression and proteomic data from non-stenotic human aortic valve interstitial cells. Lp (a) treatment induced osteogenic differentiation, extracellular remodeling, extracellular vesicles biogenesis, and apoptosis of human aortic valve interstitial cells. In particular, the Wnt/ β-catenin signalling pathway, a known calcification pathway contributing to aortic valve stenosis, was differentially expressed compared to non-treated cells. Lp (a) also induced the expression of 14-3-3 proteins known to regulate various signalling pathway relevant to aortic valve disease. Elucidating the mechanisms and molecular players that Lp (a) induces in the early stages of the disease to initiate aortic valve calcification could provide insight into potential pharmacological targets for the treatment of this debilitating disease.

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Section: Discussionmentioning

confidence: 99%

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Yu¹,

Kapur²,

Hamid³

et al. 2018

J Pharmacogenomics Pharmacoproteom

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“…Each miRNA regulates numerous mRNAs and involve multiple signaling pathways. Increasing evidences have indicated that miRNAs play multiple functions in skeletal development, bone formation and remodeling, and osteoblast differentiation, through regulation of the osteoblastic phenotype related essential signaling pathways [23,[45][46][47][48] . For example, under osteogenic differentiation, multiple miRNAs such as miR-17-5p and miR-106a that attenuate RUNX2 and SMAD signal is by suppressing BMP2 [49].…”

Section: Discussionmentioning

confidence: 99%

“…The clinical bone sample was originally from patients at the age between 55 and 70 years old. Exclusive criteria: individuals with diabetes, malignancy or other severe diseases in the previous 5 years; inclusive criteria: patients who with low-energy fractures [22,23]. All of the clinical procedures were approved by the IRB of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine.…”

Section: Methodsmentioning

confidence: 99%

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miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

Duan

Zhao

Xiong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a bone metabolic disease characterized by a systemic impairment of bone mass, which results in increased propensity of fragility fractures. A reduction in the differentiation of MSCs into osteoblasts contributes to the impaired bone formation observed in osteoporosis. Mesenchymal stem cells (MSCs) are induced to differentiate into preosteoblasts, which are regulated by the signaling cascades initiated by the various signals, including miRNAs. miR-16-2* is a newly discovered miRNA that participates in diagnosis and prognosis of hepatocellular carcinoma, cervical cancer and chronic lymphocytic leukemia. However, the effect of miR-16-2* on the regulation of osteoblast differentiation and the mechanism responsible are still unclear. Here we discuss the contribution of miR-16-2* to osteoporosis, osteoblast differentiation and mineralization. Methods: The expression pattern of miR-16-2* during osteogenesis or in osteoporosis bone samples was validated by quantitative real-time PCR (qRT-PCR). The human bone marrow mesenchymal stem cells (hBMSCs) were induced to differentiate into osteoblasts by osteogenic induced medium containing dexamethasone, ascorbate-2-phosphat, beta-glycerophosphate and vitamin-D3. The target genes of miR-16-2* were predicted by TargetScan and PicTar. The mRNA and protein levels of osteogenic key markers were detected using qRT-PCR or western blot respectively. The WNT signal activity was analyzed by TOP/FOP reporter assay. Results: The expression of miR-16-2* in patient bone tissue with osteoporosis was negatively correlated with bone formation related genes. During osteoblast differentiation process, the expression of miR-16-2* was significantly decreased. Upregulation of miR-16-2* in hBMSCs impaired the osteogenic differentiation while the downregulation of miR-16-2* increased this process. Upregulation the expression of miR-16-2* could also block the WNT signal pathway by directly target WNT5A. Furthermore, knockdown of miR-16-2* could promote the activation of RUNX2, possibly by lifting the inhibitory effect of miR-16-2* on WNT pathway. Conclusion: Taken together, we report a novel biological role of miR-16-2* in osteogenesis through regulating WNT5A response for the first time. Our data support the potential utilization of miRNA-based therapies in regenerative medicine.

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“…DEX was an anti-inflammatory drug, and was widely used in various serious disease (18). Study has reported that DEX could inhibit osteoblast differentiation (19,20). In this study, we aims to evaluate whether DEX supplementation could induce the similar effects in normal chondrocytes as LCPD chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Downregulated SOX9 mediated by miR‑206 promoted cell apoptosis in Legg-Calvï¿½-Perthes disease

Luo

Han

et al. 2017

Oncol Lett

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Abstract. Legg-Calvé-Perthes disease (LCPD) commonly onsets in adolescents, and threatens their health. However, the potential mechanism underlying LCPD remains unclear. MicroRNA (miR)-206 and SRY-box 9 (SOX9) serve an important role in chondrocytes; however, their role in LCPD remains ambiguous. In the present study, whether miR-206 and SOX9 mediated cell apoptosis in dexamethasone (DEX)-induced LCPD was investigated. The chondrocytes of the LCPD and normal control group were isolated from clinical tissues. Reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-206 and SOX9 mRNA. Western blotting was used to measure the protein level of SOX9. A combination of Annexin V-fluorescein isothiocyanate flow cytometry was used to assess cell apoptosis. The association between miR-206 and SOX9 was detected using a luciferase reporter assay. miR-206 was overexpressed while SOX9 was downregulated in chondrocytes treated with DEX obtained from patients with LCPD. miR-206 targeted SOX9 to regulate its expression. Overexpression of miR-206 promoted cell apoptosis in TC28, while it was reversed by SOX9 overexpression. TC28 cells pretreated with DEX significantly promoted cell apoptosis, while cells transfected with miR-206 inhibitor significantly reversed the effect; however, downregulated SOX9 abolished the effects of miR-206 inhibitor. SOX9 mediated by miR-206 possibly contributed to the pathogenesis of LCPD. The results of the present study suggest that miR-206 and SOX9 function as important therapeutic targets for the future of clinical therapy.

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miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway

Cited by 116 publications

References 58 publications

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells

Downregulated SOX9 mediated by miR‑206 promoted cell apoptosis in Legg-Calvï¿½-Perthes disease

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