Dataset Information

Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137.

ABSTRACT:

Background

Osteoporosis (OP) is one of the commonly seen bone diseases with low bone mineral densities and trauma fractures. Accumulative studies have demonstrated that the occurrence of OP is closely related to osteoclasts differentiation. LncRNA FTX has been demonstrated to inhibit the development of some human cancers. However, its potential functions in human OP remains to be elusive.

Methods

The expressions of FTX and miR-137 in bone and serum samples of patients with or without OP were measured. Bioinformatics analysis, RIP assays and luciferase reporter assays were performed to examine the upstream and downstream transactional factors of miR-137. Functional assays were conducted to check the roles of the Notching1 signaling pathway OP.

Results

FTX was suppressed in OP samples and serums, however, miR-137 was greatly elevated. FTX reduced osteoclast-genesis and inhibited osteogenic differentiation by targeting miR-137. This also inhibited the Notch1 signaling pathway.

Conclusion

Our experiments and results pointed out that lncRNA FTX up-regulated miR-137 in OP through the Notch1 signaling pathway.

SUBMITTER: Yu Y

PROVIDER: S-EPMC7359489 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137.

Yu Yingfeng Y Yao Peiquan P Wang Zhikun Z Xie Wenwei W

BMC musculoskeletal disorders 20200713 1

<h4>Background</h4>Osteoporosis (OP) is one of the commonly seen bone diseases with low bone mineral densities and trauma fractures. Accumulative studies have demonstrated that the occurrence of OP is closely related to osteoclasts differentiation. LncRNA FTX has been demonstrated to inhibit the development of some human cancers. However, its potential functions in human OP remains to be elusive.<h4>Methods</h4>The expressions of FTX and miR-137 in bone and serum samples of patients with or with ...[more]

PMID: 32660465

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Project description:PurposeAs the global population ages rapidly, osteoporotic fractures have become an important public health problem. Previous studies have suggested that miR-137 is involved in the regulation of bone formation, but its specific regulatory mechanism remains unclear. In this study, we aimed to explore the expression, role, and regulatory mechanism of miR-137 in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs).MethodshBMSCs were induced into osteoblasts at first, and the expression level of miR-137 at different time points was detected. After knockdown and overexpression of miR-137, the effect of miR-137 on the osteogenic differentiation of hBMSCs was examined through alkaline phosphatase (ALP) staining and Alizarin Red staining. Western blotting was performed to detect the expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. Bioinformatics websites were used to predict the target binding sites for miR-137 and KDM4A, and the results were validated using luciferase reporter gene experiments. Moreover, the ALP activity, calcium nodule formation, and activation of Runx2, OCN, and TLR4/NF-κB pathways were observed after knockdown of KDM4A.ResultsThe expression of miR-137 decreased during osteogenic differentiation. Knockdown of miR-137 expression increased the osteogenic ability of hBMSCs, while overexpression of it weakened the ability. Through the activation of the TLR4/NF-κB pathway, miR-137 inhibited osteogenic differentiation. KDM4A was identified as a predicted target gene of miR-137. After knocking down KDM4A expression, the osteogenic ability of hBMSCs was diminished, and the TLR4/NF-κB pathway was activated. Furthermore, the osteogenic ability of hBMSCs was partially restored and the activation level of TLR4/NF-κB was reduced after miR-137 knockdown.ConclusionMiR-137 enhances the activity of the TLR4/NF-κB pathway by targeting KDM4A, thereby inhibiting the osteogenic differentiation of hBMSCs and exacerbating osteoporosis.

Project description:GBM (Glioblastoma multiform) is the most malignant tumor type of the central nervous system and has poor diagnostic and clinical outcomes. LncRNAs (Long non-coding RNAs) have been reported to participate in multiple biological and pathological processes, but their underlying mechanism remains poorly understood. Here, we aimed to explore the role of the lncRNA HAS2-AS1 (HAS2 antisense RNA 1) in GBM. GSE103227 was analyzed, and qRT-PCR was performed to measure the expression of HAS2-AS1 in GBM. FISH (Fluorescence in situ hybridization) was performed to verify the localization of HAS2-AS1. The interaction between HAS2-AS1 and miR-137 (microRNA-137) was predicted by LncBook and miRcode followed by dual-luciferase reporter assays, and the relationships among HAS2-AS1, miR-137 and LSD1 (lysine-specific demethylase 1) were assessed by WB (western blot) and qRT-PCR. Colony formation and CCK-8 (cell counting kit-8) assays were performed as functional tests. In vivo, nude mice were used to confirm the function of HAS2-AS1. HAS2-AS1 expression was upregulated in GBM cell lines, and HAS2-AS1 was localized mainly in the cytoplasm. In vitro, high HAS2-AS1 expression promoted proliferation, and knockdown of HAS2-AS1 significantly inhibited proliferation. Furthermore, HAS2-AS1 functioned as a ceRNA (competing endogenous RNA) of miR-137, leading to the disinhibition of its downstream target LSD1. The miR-137 level was downregulated by HAS2-AS1 overexpression and upregulated by HAS2-AS1 knockdown. In a subsequent study, LSD1 expression was negatively regulated by miR-137, while miR-137 reversed the LSD1 expression levels caused by HAS2-AS1. These results were further supported by the nude mouse tumorigenesis experiment; compared with xenografts with high HAS2-AS1 expression, the group with low levels of HAS2-AS1 exhibited suppressed proliferation and better survival. We conclude that lncRNA HAS2-AS1 promotes proliferation by functioning as a miR-137 decoy to increase LSD1 levels and thus might be a possible biomarker for GBM.

Dataset Information

Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137.

Background

Methods

Results

Conclusion

Publications

Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137.

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