MECHANISMS IN ENDOCRINOLOGY: Micro-RNAs: targets for enhancing osteoblast differentiation and bone formation

Taipaleenmäki, Hanna; Hokland, Lea Bjerre; Chen, Li; Kauppinen, Sakari; Kassem, Moustapha

doi:10.1530/eje-11-0646

Cited by 126 publications

(87 citation statements)

References 141 publications

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“…Our study showed that miR-93 was involved in osteoblast mineralization and exerted its roles through interaction with the bone-specific factor Sp7. miRNAs made contributions in osteoblast differentiation, (20) but the mechanisms of their actions in osteoblast mineralization have not been clearly shown. In the present study, microarray analysis revealed that miR-93 exhibited maximal change during osteoblast 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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“…Computational prediction of targets relies on the pairing of the seed sequence of the miRNA to a complementary 3 0 UTR following strict base-pairing rules. 42 In the current study, several important binding sites of miR-152 to the 3 0 UTR of DKK1 mRNA were identified. DKK1 has been reported to be overexpressed in MM and in other cancers such as hepatoblastoma, Wilm's tumors and breast cancer.…”

Section: Discussionmentioning

confidence: 67%

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

Chen

George

et al. 2015

RNA Biology

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Multiple myeloma (MM) induced bone lesion is one of the most crippling characteristics, and the MM secreted Dickkopf-1 (DKK1) has been reported to play important role in this pathologic process. However, the underlying regulation mechanisms involved in DKK1 expression are still unclear. In this study, we validated the expression patterns of microRNA (miR) 15a, 34a, 152, and 223 in MM cells and identified that miR-152 was significantly downregulated in the MM group compared with the non-MM group, and that miR-152 level was negatively correlated with the expression of DKK1 in the MM cells. Mechanistic studies showed that manipulating miR-152 artificially in MM cells led to changes in DKK-1 expression, and miR-152 blocked DKK1 transcriptional activity by binding to the 3 0 UTR of DKK1 mRNA. Importantly, we revealed that MM cells stably expressing miR-152 improved the chemotherapy sensitivity, and counteracted the bone disruption in an intrabone-MM mouse model. Our study contributes better understanding of the regulation mechanism of DKK-1 in MM, and opens up the potential for developing newer therapeutic strategies in the MM treatment.

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“…Con, control; Dex, dexamethasone; NC, negative control; miR, microRNA. Ma et al 2012, Taipaleenmaki et al 2012, Wei et al 2012, Xu et al 2012a,b, Chiyomaru et al 2013. Furthermore, these miRNAs could mediate WNT signaling (Chiyomaru et al 2013, Nagano et al 2013, Guo et al 2014, Rathod et al 2014, Hashemi et al 2015, a crucial factor in decreased bone formation in response to GCs.…”

Section: Discussionmentioning

confidence: 99%

“…miRNAs may also promote the translation of selected mRNAs in a cell-cycle-phase-dependent way (Zeng 2006). Results of recent studies have indicated that some miRNAs, such as miR-27a, miR-29a, miR-34a, miR-125b, miR-133, miR-138, miR-199a, miR-206, miR-338, miR-335, and miR-378, play a crucial role in bone formation (Taipaleenmaki et al 2012). Furthermore, results of previous studies have indicated that many of these miRNAs, including miR-27a, miR-29a, miR-34a, miR-125b, miR-199a, and miR-574, could mediate cell proliferation , Ma et al 2012, Wei et al 2012, Xu et al 2012a,b, Chiyomaru et al 2013.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

Shi¹,

Huang²,

Kang³

et al. 2015

Journal of Molecular Endocrinology

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The inhibition of osteoblast proliferation by glucocorticoids (GCs) is very important in the etiology of GC-induced osteoporosis. The mechanisms of this process are still not fully understood. The results of recent studies have indicated an important role for microRNAs in GC-mediated responses in various cellular processes, including cell proliferation and apoptosis. Therefore, we developed the hypothesis that these regulatory molecules might be involved in GC-decreased osteoblast proliferation. Western blotting, quantitative realtime PCR, cell proliferation assays, and luciferase assays were employed to investigate the role of miRNAs in GC-inhibited osteoblast proliferation. microRNA-199a-5p was significantly increased in osteoblasts treated with dexamethasone (Dex). To delineate the role of microRNA-199a-5p, we silenced and overexpressed microRNA-199a-5p in osteoblasts. We found that overexpressing microRNA-199a-5p remarkably increased the inhibition effect of Dex on osteoblast proliferation, and depleting microRNA-199a-5p significantly attenuated Dex-inhibited osteoblast proliferation. Results of mechanistic studies indicated that microRNA-199a-5p inhibited FZD4 and WNT2 expression through a microRNA-199a-5p binding site within the 3 0 -UTR of FZD4 and WNT2. The post-transcriptional repression of FZD4 and WNT2 were further confirmed by luciferase reporter assay. These results indicated that microRNA-199a-5p may play a significant role in GC-inhibited osteoblast proliferation by regulating the WNT signaling pathway.

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MECHANISMS IN ENDOCRINOLOGY: Micro-RNAs: targets for enhancing osteoblast differentiation and bone formation

Cited by 126 publications

References 141 publications

miR-93/Sp7 function loop mediates osteoblast mineralization

miR-93/Sp7 function loop mediates osteoblast mineralization

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

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