Circ_0008542 in osteoblast exosomes promotes osteoclast-induced bone resorption through m6A methylation
Open Access
- 18 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (7), 1-13
- https://doi.org/10.1038/s41419-021-03915-1
Abstract
With an increasing aging society, China is the world’s fastest growing markets for oral implants. Compared with traditional oral implants, immediate implants cause marginal bone resorption and increase the failure rate of osseointegration, but the mechanism is still unknown. Therefore, it is important to further study mechanisms of tension stimulus on osteoblasts and osteoclasts at the early stage of osseointegration to promote rapid osseointegration around oral implants. The results showed that exosomes containing circ_0008542 from MC3T3-E1 cells with prolonged tensile stimulation promoted osteoclast differentiation and bone resorption. Circ_0008542 upregulated Tnfrsf11a (RANK) gene expression by acting as a miR-185-5p sponge. Meanwhile, the circ_0008542 1916-1992 bp segment exhibited increased m6A methylation levels. Inhibiting the RNA methyltransferase METTL3 or overexpressing the RNA demethylase ALKBH5 reversed osteoclast differentiation and bone resorption induced by circ_0008542. Injection of circ_0008542 + ALKBH5 into the tail vein of mice reversed the same effects in vivo. Site-directed mutagenesis study demonstrated that 1956 bp on circ_0008542 is the m6A functional site with the abovementioned biological functions. In conclusion, the RNA methylase METTL3 acts on the m6A functional site of 1956 bp in circ_0008542, promoting competitive binding of miRNA-185-5p by circ_0008542, and leading to an increase in the target gene RANK and the initiation of osteoclast bone absorption. In contrast, the RNA demethylase ALKBH5 inhibits the binding of circ_0008542 with miRNA-185-5p to correct the bone resorption process. The potential value of this study provides methods to enhance the resistance of immediate implants through use of exosomes releasing ALKBH5.Keywords
Funding Information
- China Postdoctoral Science Foundation (2020M671162)
This publication has 39 references indexed in Scilit:
- Circular RNA CDR1as regulates osteoblastic differentiation of periodontal ligament stem cells via the miR-7/GDF5/SMAD and p38 MAPK signaling pathwayStem Cell Research & Therapy, 2018
- Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast–Osteoblasts Communication in Bone RemodelingFrontiers in Physiology, 2018
- METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A ModificationCell Stem Cell, 2017
- Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation controlNature, 2017
- Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formationNature Communications, 2016
- Circular RNAs: a new frontier in the study of human diseasesJournal of Medical Genetics, 2016
- N6-methyladenosine marks primary microRNAs for processingNature, 2015
- m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to PluripotencyCell Stem Cell, 2015
- circRNA Biogenesis Competes with Pre-mRNA SplicingMolecular Cell, 2014
- A View of Pre-mRNA Splicing from RNase R Resistant RNAsInternational Journal of Molecular Sciences, 2014