A microRNA regulatory mechanism of osteoblast differentiation

Inose, Hiroyuki; Ochi, Hiroki; Kimura, Ayako; Fujita, Koji; Xu, Ren; Sato, Shingo; Iwasaki, Makiko; Sunamura, Satoko; Takeuchi, Yasuhiro; Fukumoto, Seiji; Saito, Kuniaki; Nakamura, Takashi; Siomi, Haruhiko; Ito, Hiroshi; Arai, Yoshiyasu; Shinomiya, K.; Takeda, Satoshi

doi:10.1073/pnas.0909311106

Cited by 270 publications

(213 citation statements)

References 45 publications

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“…(34) miR-206 regulated osteoblast differentiation by targeting Cx43. (35) miR-93 and Sp7 worked along with those regulatory factors, and played their roles in osteoblast differentiation and mineralization.…”

Section: Discussionmentioning

confidence: 99%

miR-93/Sp7 function loop mediates osteoblast mineralization

Yang

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

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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Section: Discussionmentioning

confidence: 99%

miR-93/Sp7 function loop mediates osteoblast mineralization

Yang

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

101

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“…20 The miR-206 expression was shown to inhibit osteoblast development, whereas miR-206 knockdown promoted differentiation. 21 Many additional miRNAs have been shown to play a role in osteogenesis (see Figure 1a and Table 1). …”

Section: A Central Role For Mirnas In Bone Homeostasismentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

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“…miR-125b has been shown to inhibit osteoblast differentiation in the mouse MSC line ST2 (17), whereas miR-133 and -135 directly target Runx2 and Smad5, respectively, and inhibit differentiation of osteoprogenitors of C2C12 mesenchymal cells (18). Moreover, miR-141 and -200a were recently found to be involved in preosteoblast differentiation through regulation of their common target Dlx5 (19), whereas miR-206 inhibits osteogenesis in vitro and in vivo by targeting Cx43 (20). Additionally, miR-29b and -2861 were characterized as positive regulators by targeting inhibitors of osteoblast differentiation (21,22).…”

mentioning

confidence: 99%

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

Eskildsen

Taipaleenmäki

Stenvang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

444

354

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Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3′ UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.regulatory RNA | bone biology | osteoblastic differentiation

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A microRNA regulatory mechanism of osteoblast differentiation

Cited by 270 publications

References 45 publications

miR-93/Sp7 function loop mediates osteoblast mineralization

miR-93/Sp7 function loop mediates osteoblast mineralization

MicroRNAs as regulators of bone homeostasis and bone metastasis

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

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