A Runx2/miR-3960/miR-2861 Regulatory Feedback Loop during Mouse Osteoblast Differentiation

Hu, Rong; Liu, Wei; Li, Hui; Yang, Li; Chen, Chao; Xia, Zhuying; Guo, Lijuan; Xie, Hui; Zhou, Hong-Hao; Wu, Xianping; Luo, Xi

doi:10.1074/jbc.m110.176099

Cited by 215 publications

(174 citation statements)

References 33 publications

(37 reference statements)

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“…miRNAs play a key role in various biological processes including osteoblast differentiation and mineralization. (29)(30)(31) Osteoclastogenesis is also regulated by miRNAs. In the present study, we performed microarray assays and found miR-148a dramatically upregulated during osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 99%

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

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MicroRNAs (miRNAs) play crucial roles in bone metabolism. In the present study, we found that miR-148a is dramatically upregulated during osteoclastic differentiation of circulating CD14þ peripheral blood mononuclear cells (PBMCs) induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL). Overexpression of miR-148a in CD14þ PBMCs promoted osteoclastogenesis, whereas inhibition of miR-148a attenuated osteoclastogenesis. V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is a transcription factor negatively regulating RANKL-induced osteoclastogenesis. miR-148a directly targeted MAFB mRNA by binding to the 3 0 untranslated region (3 0 UTR) and repressed MAFB protein expression. In vivo, our study showed that silencing of miR-148a using a specific antagomir-inhibited bone resorption and increased bone mass in mice receiving ovariectomy (OVX) and in sham-operated control mice. Furthermore, our results showed that miR-148a levels significantly increased in CD14þ PBMCs from lupus patients and resulted in enhanced osteoclastogenesis, which contributed to the lower bone mineral density (BMD) in lupus patients compared with normal controls. Thus, our study provides a new insight into the roles of miRNAs in osteoclastogenesis, and contributes to a new therapeutic pathway for osteoporosis. ß

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Section: Discussionmentioning

confidence: 99%

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

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176

130

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“…Interestingly, other clusters have also been studied, such as the auto-regulatory feedback loops controlling Runx2 expression. miR-3960/-2861 is transactivated by Runx2 in vitro, thereby maintaining its own levels of expression by blocking the expression of Hoxa and Hdac5, negative regulators of osteoblast differentiation (Kanzler et al 1998, Dobreva et al 2006, Li et al 2009a, Hu et al 2011. Furthermore, an in vivo approach has demonstrated that Satb2 is also targeted by miR-34s, affecting osteoblast proliferation mainly by means of miR-34b and miR-34c.…”

Section: Mirnas and Osteoblast Differentiationmentioning

confidence: 99%

“…It has also been suggested that a decrease in miR-2861 expression contributes to OP. miR-2861 has already been shown to be a BMP-induced miRNA, targeting Hdac5 and therefore involved in Runx2 degradation (Li et al 2009a, Hu et al 2011. Li et al (2009a) have shown that inhibition of miR-2861, using a specific antisense oligonucleotide introduced by a single tail vein injection, leads to decreased bone mass, reduced osteoblast activity, and osteoblast marker alteration in mice.…”

Section: The Interplay Between Mirnas and Wnt/b-catenin Signalingmentioning

confidence: 99%

MicroRNAs and post-transcriptional regulation of skeletal development

Gámez¹,

Rodríguez-Carballo²,

Ventura³

2014

Journal of Molecular Endocrinology

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MicroRNAs (miRNAs) have become integral nodes of post-transcriptional control of genes that confer cellular identity and regulate differentiation. Cell-specific signaling and transcriptional regulation in skeletal biology are extremely dynamic processes that are highly reliant on dose-dependent responses. As such, skeletal cell-determining genes are ideal targets for quantitative regulation by miRNAs. So far, large amounts of evidence have revealed a characteristic temporal miRNA signature in skeletal cell differentiation and confirmed the essential roles that numerous miRNAs play in bone development and homeostasis. In addition, microarray expression data have provided evidence for their role in several skeletal pathologies. Mouse models in which their expression is altered have provided evidence of causal links between miRNAs and bone abnormalities. Thus, a detailed understanding of the function of miRNAs and their tight relationship with bone diseases would constitute a powerful tool for early diagnosis and future therapeutic approaches.

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“…(8) Our previous studies also identified two new miRNAs (miR-2861/ miR-3960 cluster) in mouse osteoblasts that promoted osteoblast differentiation by repressing histone deacetylase 5 (HDAC5) and homeobox A2 (Hoxa2) expression at the posttranscriptional level. (9,10) However, the functions of miRNAs in osteoblast mineralization need further investigation.…”

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confidence: 99%

miR-93/Sp7 function loop mediates osteoblast mineralization

Yang

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

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101

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microRNAs (miRNAs) play pivotal roles in osteoblast differentiation. However, the mechanisms of miRNAs regulating osteoblast mineralization still need further investigation. Here, we performed miRNA profiling and identified that miR-93 was the most significantly downregulated miRNA during osteoblast mineralization. Overexpression of miR-93 in cultured primary mouse osteoblasts attenuated osteoblast mineralization. Expression of the Sp7 transcription factor 7 (Sp7, Osterix), a zinc finger transcription factor and critical regulator of osteoblast mineralization, was found to be inversely correlated with miR-93. Then Sp7 was confirmed to be a target of miR-93. Overexpression of miR-93 in cultured osteoblasts reduced Sp7 protein expression without affecting its mRNA level. Luciferase reporter assay showed that miR-93 directly targeted Sp7 by specifically binding to the target coding sequence region (CDS) of Sp7. Experiments such as electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and promoter luciferase reporter assay confirmed that Sp7 bound to the promoter of miR-93. Furthermore, overexpression of Sp7 reduced miR-93 transcription, whereas blocking the expression of Sp7 promoted miR-93 transcription. Our study showed that miR-93 was an important regulator in osteoblast mineralization and miR-93 carried out its function through a novel miR-93/Sp7 regulatory feedback loop. Our findings provide new insights into the roles of miRNAs in osteoblast mineralization. ß

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A Runx2/miR-3960/miR-2861 Regulatory Feedback Loop during Mouse Osteoblast Differentiation

Cited by 215 publications

References 33 publications

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

MicroRNAs and post-transcriptional regulation of skeletal development

miR-93/Sp7 function loop mediates osteoblast mineralization

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