MicroRNA-29b Enhances Osteoclast Survival by Targeting BCL-2-Modifying Factor after Lipopolysaccharide Stimulation

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Abstract

Recent findings suggest that microRNAs (miRs) play a critical role in osteoclastogenesis, which regulates bone loss. We hypothesized that inflammation induces miR-29b, which increases the survival rate in osteoclasts (OCs), leading to bone loss. The expression level of miR-29b increased in OC stimulated by lipopolysaccharide (LPS) in an in vitro system which correlated with its increase in tibiae from mice that received LPS injections compared with those that received vehicle treatment. An miR-29b mimic increased OC survival rate without any change in OC differentiation, and furthermore, the inhibition of endogenous miR-29b induced by LPS decreased OC survival rate. Increased OC survival rate after overexpression of miR-29b was associated with antiapoptotic activity, as shown by staining annexin V-positive cells. We found that a target gene of miR-29b is BCL-2-modifying factor ( Bmf), which acts as a proapoptotic factor, and that miR-29b binds to the 3′-UTR of Bmf. Our data demonstrate that LPS-induced miR-29b increases the number of OC by enhancing OC survival through decreased BMF.

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Most cited references 23

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miR-34a Blocks Osteoporosis and Bone Metastasis by Inhibiting Osteoclastogenesis and Tgif2

Jing Krzeszinskia, Wei Wei, HoangDinh Huynh … (2014)

The bone resorbing osteoclasts significantly contribute to osteoporosis and cancer bone metastases 1-3 . MicroRNAs (miRNAs) play important roles in physiology and disease 4,5 , and present tremendous therapeutic potential 6 . Nonetheless, how miRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is down-regulated during osteoclast differentiation. Osteoclastic miR-34a over-expressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify Tgif2 (transforming growth factor-beta-induced factor 2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.

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A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii.

Yijun Qi, G Hannon, Shan Li … (2007)

Endogenous small RNAs function in RNA interference (RNAi) pathways to control gene expression through mRNA cleavage, translational repression, or chromatin modification. Plants and animals contain many microRNAs (miRNAs) that play vital roles in development, including helping to specify cell type and tissue identity. To date, no miRNAs have been reported in unicellular organisms. Here we show that Chlamydomonas reinhardtii, a unicellular green alga, encodes many miRNAs. We also show that a Chlamydomonas miRNA can direct the cleavage of its target mRNA in vivo and in vitro. We further show that the expression of some miRNAs/Candidates increases or decreases during Chlamydomonas gametogenesis. In addition to miRNAs, Chlamydomonas harbors other types of small RNAs including phased small interfering RNAs (siRNAs) that are reminiscent of plant trans-acting siRNAs, as well as siRNAs originating from protein-coding genes and transposons. Our findings suggest that the miRNA pathway and some siRNA pathways are ancient mechanisms of gene regulation that evolved prior to the emergence of multicellularity.

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miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop.

Kristina Kapinas, Anne Delany, Tinisha Ricks … (2010)

Differentiation of human mesenchymal stem cells into osteoblasts is controlled by extracellular cues. Canonical Wnt signaling is particularly important for maintenance of bone mass in humans. Post-transcriptional regulation of gene expression, mediated by microRNAs, plays an essential role in the control of osteoblast differentiation. Here, we find that miR-29a is necessary for human osteoblast differentiation, and miR-29a is increased during differentiation in the mesenchymal precursor cell line hFOB1.19 and in primary cultures of human osteoblasts. Furthermore, the promoter of the expressed sequence tag containing the human miR-29a gene is induced by canonical Wnt signaling. This effect is mediated, at least in part, by two T-cell factor/LEF-binding sites within the proximal promoter. Furthermore, we show that the negative regulators of Wnt signaling, Dikkopf-1 (Dkk1), Kremen2, and secreted frizzled related protein 2 (sFRP2), are direct targets of miR-29a. Endogenous protein levels for these Wnt antagonists are increased in cells transfected with synthetic miR-29a inhibitor. In contrast, transfection with miR-29a mimic decreases expression of these antagonists and potentiates Wnt signaling. Overall, we demonstrate that miR-29 and Wnt signaling are involved in a regulatory circuit that can modulate osteoblast differentiation. Specifically, canonical Wnt signaling induces miR-29a transcription. The subsequent down-regulation of key Wnt signaling antagonists, Dkk1, Kremen2, and sFRP2, by miR-29a potentiates Wnt signaling, contributing to a gene expression program important for osteoblast differentiation. This novel regulatory circuit provides additional insight into how microRNAs interact with signaling molecules during osteoblast differentiation, allowing for fine-tuning of intricate cellular processes.

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Author and article information

Contributors

Hye-Seon Choi:

ORCID: http://orcid.org/0000-0003-2992-2677

Journal

Journal ID (nlm-ta): Oxid Med Cell Longev

Journal ID (iso-abbrev): Oxid Med Cell Longev

Journal ID (publisher-id): OMCL

Title: Oxidative Medicine and Cellular Longevity

Publisher: Hindawi

ISSN (Print): 1942-0900

ISSN (Electronic): 1942-0994

Publication date Collection: 2019

Publication date (Electronic): 10 April 2019

Volume: 2019

Electronic Location Identifier: 6018180

Affiliations

¹Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea

²Department of Pathology, Ulsan University Hospital, Ulsan 682-714, Republic of Korea

Author notes

Academic Editor: Ryuichi Morishita

Author information

Hye-Seon Choi http://orcid.org/0000-0003-2992-2677

Article

DOI: 10.1155/2019/6018180

PMC ID: 6481009

PubMed ID: 31093317

SO-VID: 8fba2ce7-d7bc-46b2-b7d7-83a5070d7801

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 7 November 2018

Date revision received : 11 January 2019

Date accepted : 12 February 2019

Funding

Funded by: Ministry of Health and Welfare

Award ID: HI18C0375

Funded by: National Research Foundation

Award ID: 2018R1A2B6001276

Award ID: 2016R1A6A3A11932375

Award ID: 2014R1A6A1030318

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