HOXA cluster gene expression during osteoblast differentiation involves epigenetic control

Silva, Rodrigo A. da; Fuhler, Gwenny M.; Janmaat, Vincent T.; Fernandes, Célio Júnior da Costa; Feltran, Geórgia da Silva; Oliveira, Flávia Amadeu de; Matos, Adriana Arruda; Oliveira, Rodrigo Cardoso de; Ferreira, Marcel Rodrigues; Zambuzzi, Willian Fernando; Peppelenbosch, Maikel P.

doi:10.1016/j.bone.2019.04.026

Cited by 33 publications

(20 citation statements)

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“…In addition, the expression level of HOXA7 protein in hBMSCs transfected with miR-920 mimic was detected, and it was found that the transfected miR-920 inhibitor significantly increased the expression level of HOXA7 protein, which further confirms the direct effect of miR-920 on HOXA7. A study by da Silva et al [23] demonstrated that HOXA cluster gene expression was increased during osteoblast differentiation, which is consistent with our conclusion. Previous Fig.…”

Section: Discussionsupporting

confidence: 93%

MiR-920 promotes osteogenic differentiation of human bone mesenchymal stem cells by targeting HOXA7

Zha

Wang

2020

J Orthop Surg Res

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Background: To explore the effect of miR-920 on osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) and the possible mechanism. Methods: Osteoporosis (OP) and healthy control bone tissues were collected, and the relative expression of miR-920 and HOXA7 was measured. hBMSCs were isolated and cultured in vitro. Alkaline phosphatase activity and miR-920 and HOXA7 relative expression were measured during osteogenic differentiation of hBMSCs. Then, bioinformatic analysis was performed to assess the potential mechanism of miR-920. MiR-920 mimic and inhibitor were introduced into hBMSCs by lipofection transfection and were used to investigate the effect of miR-920 on the osteogenic differentiation of hBMSCs. A dual luciferase reporter assay was used to identify whether the 3′UTR of HOXA7 mRNA was a direct target of miR-920. Western blotting was performed to assess whether miR-920 affected the MAPK signaling pathway. Results: We found that miR-920 was downregulated in OP patients compared with controls, while HOXA7 was upregulated, and miR-920 had a negative correlation with HOXA7 (r = − 0.859, P = 0.001). Moreover, miR-920 was increased during osteogenic differentiation of hBMSCs, while HOXA7 had the opposite tendency. Bioinformatic analysis revealed that there were a total of 207 target genes, and MAPK was a potential targeted signaling pathway. MiR-920 mimic significantly increased ALP activity, calcium deposition, osteoblastic protein expression (ALP and OSX), and p-p38 and p-JNK protein levels. Conclusion: Overall, miR-920 promotes osteogenic differentiation of hBMSCs by targeting HOXA7 through the MAPK signaling pathway.

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Section: Discussionsupporting

confidence: 93%

MiR-920 promotes osteogenic differentiation of human bone mesenchymal stem cells by targeting HOXA7

Zha

Wang

2020

J Orthop Surg Res

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“…Interestingly, many genes of the Homeobox family displayed both epigenetic and transcriptional dysregulation in patient MSCs, and these changes were observed in earlier stages of disease. In this regard, members of the HOX family have been recently described to be key drivers of OB differentiation, in which their expression is fine-tuned by demethylation of their promoters during the osteogenic process 54 . Furthermore, we observed that healthy MSCs exposed to MM cells, similar to what was observed in patient MSCs, not only displayed an altered methylome, but also showed impaired MSC-to-OB differentiation, as previously described 20 .…”

Section: Discussionmentioning

confidence: 99%

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

García-Gómez

Rodríguez-Ubreva

et al. 2019

Preprint

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and agarciag@carrerasresearch.org Running title: Reverting DNA methylation to treat MM bone disease Abbreviations: mesenchymal stromal cells, osteoblast, multiple myeloma, DNA methylation Abstract word count: 212 Word count: 3999 Figure count: 5 Reference count: 60 ABSTRACT Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on the bone marrow (BM) microenvironment, in particular on mesenchymal stromal cells (MSCs). MSCs from MM patients exhibit an abnormal transcriptional profile, suggesting that epigenetic alterations could be governing the tumor-promoting functions of MSCs and their prolonged osteoblast (OB) suppression in MM. In this study, we analyzed the DNA methylome of BM-derived MSCs from patients with monoclonal gammopathy of undetermined significance, smoldering myeloma and symptomatic MM at diagnosis in comparison with their normal counterparts. DNA methylation alterations were found at each of the myeloma stage in association with deregulated expression levels of Homeobox genes involved in osteogenic differentiation. Moreover, these DNA methylation changes were recapitulated in vitro by exposing MSCs from healthy individuals to MM plasma cells. Pharmacological targeting of DNMTs and G9a with the dual inhibitor CM-272, reverted the expression of aberrantly methylated osteogenic regulators and promoted OB differentiation of MSCs from myeloma patients. Most importantly, in a mouse model of bone marrow-disseminated MM, administration of CM-272 prevented tumor-associated bone loss and reduced tumor burden. Our results demonstrated that not only was aberrant DNA methylation a main contributor to bone formation impairment found in MM patients, but also its targeting by CM-272 was able to reverse MM-associated bone loss.

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“…Long non-coding RNA Growth Arrest-Specific 5 (GAS5) has also been identified as a ceRNA that promotes MMPs by sponging miR-21 during OA (Song et al, 2014). Previous studies identified HOTTIP as an important regulator in OA and small cell lung cancer chemoresistance and osteoblast differentiation (Kim et al, 2013; Sun Y. et al, 2018; Da et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA HOTTIP Promotes CCL3 Expression and Induces Cartilage Degradation by Sponging miR-455-3p

Mao

Kang

Lin

et al. 2019

Front. Cell Dev. Biol.

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Long non-coding RNAs (lncRNAs) play pivotal roles in diseases such as osteoarthritis (OA). However, knowledge of the biological roles of lncRNAs is limited in OA. We aimed to explore the biological function and molecular mechanism of HOTTIP in chondrogenesis and cartilage degradation. We used the human mesenchymal stem cell (hMSC) model of chondrogenesis, in parallel with, tissue biopsies from normal and OA cartilage to detect HOTTIP, CCL3, and miR-455-3p expression in vitro . Biological interactions between HOTTIP and miR-455-3p were determined by RNA silencing and overexpression in vitro . We evaluated the effect of HOTTIP on chondrogenesis and degeneration, and its regulation of miR-455-3p via competing endogenous RNA (ceRNA). Our in vitro ceRNA findings were further confirmed within animal models in vivo . Mechanisms of ceRNAs were determined by bioinformatic analysis, a luciferase reporter system, RNA pull-down, and RNA immunoprecipitation (RIP) assays. We found reduced miR-455-3p expression and significantly upregulated lncRNA HOTTIP and CCL3 expression in OA cartilage tissues and chondrocytes. The expression of HOTTIP and CCL3 was increased in chondrocytes treated with interleukin-1β (IL-1β) in vitro . Knockdown of HOTTIP promoted cartilage-specific gene expression and suppressed CCL3. Conversely, HOTTIP overexpression reduced cartilage-specific genes and increased CCL3. Notably, HOTTIP negatively regulated miR-455-3p and increased CCL3 levels in human primary chondrocytes. Mechanistic investigations indicated that HOTTIP functioned as ceRNA for miR-455-3p enhanced CCL3 expression. Taken together, the ceRNA regulatory network of HOTTIP/miR-455-3p/CCL3 plays a critical role in OA pathogenesis and suggests HOTTIP is a potential target in OA therapy.

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HOXA cluster gene expression during osteoblast differentiation involves epigenetic control

Cited by 33 publications

References 50 publications

MiR-920 promotes osteogenic differentiation of human bone mesenchymal stem cells by targeting HOXA7

MiR-920 promotes osteogenic differentiation of human bone mesenchymal stem cells by targeting HOXA7

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Long Non-coding RNA HOTTIP Promotes CCL3 Expression and Induces Cartilage Degradation by Sponging miR-455-3p

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