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.
Highlights
Maximizing osseointegration is the key factor in successful implant placement
Current research has tension stimulation, cytomembrane characteristic proteins of confirmed that circRNAs participate in the regulation of bone HSP70, TSG101, and CD63 were positive in MC3T3-E1 cell lysates remodeling through the miRNA-mRNA axis in the form of and exosomes; cell nucleus characteristic proteins of TFIIB and molecular sponges [19,20,21]
Clinical studies have shown that this loaded method simultaneously causes marginal bone resorption and increases the failure rate of osseointegration
Summary
Maximizing osseointegration is the key factor in successful implant placement. At the interface where osseointegration occurs, osteoclast-induced bone resorption and osteoblast-induced bone formation are in a dynamic balance. Current research has tension stimulation, cytomembrane characteristic proteins of confirmed that circRNAs participate in the regulation of bone HSP70, TSG101, and CD63 were positive in MC3T3-E1 cell lysates remodeling through the miRNA-mRNA axis in the form of and exosomes; cell nucleus characteristic proteins of TFIIB and molecular sponges [19,20,21]. Regardless of whether exosomes were from the groups with or without tension stimulation, there was no change in expression of Rrp, the host gene of circ_0008542, in RAW264.7 cells, indicating that the mature miRNA after transcription; M6A modification on circRNA promotes circRNA translation [28,29,30]. Western blotting revealed that expression levels of c-fos, NFATc1, RANK, and NFκB p-P65
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