Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment

Abstract

Background Periodontal ligament stem cells (PDLSCs) are the ideal seed cells for periodontal tissue regeneration. It is well established that persistent inflammation significantly impairs the osteogenic differentiation capability of PDLSCs. Therefore, maintaining PDLSC osteogenic potential under the inflammatory microenvironment is important for treating bone loss in periodontitis. The aim of our study was to explore the potential role of circular RNA BIRC6 (circBIRC6) in regulating osteogenic differentiation of PDLSCs in the inflammatory conditions. Methods Alkaline phosphatase staining, Alizarin Red staining, quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining were used to evaluated the effects of circBIRC6 on the osteogenic differentiation of PDLSCs. RNA pull-down and luciferase assays were performed to explore the interaction between circBIRC6 and miR-543. Then, the downstream signaling pathway affected by circBIRC6/miR-543 axis was further investigated. Results The expression level of circBIRC6 was higher in PDLSCs exposed to inflammatory stimulus and in periodontitis tissues compared to the respective controls. Downregulation of circBIRC6 enhanced the osteogenic potential of PDLSCs under the inflammatory conditions, and upregulation of circBIRC6 led to opposite findings. Mechanistically, we found that circBIRC6 modulated PDLSC osteogenic differentiation through sponging miR-543. More importantly, we have demonstrated that circBIRC6/miR-543 axis regulated the mineralization capacity of PDLSCs via PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. Conclusions In summary, the expression of miR-543 is significantly increased following circBIRC6 downregulation, leading to inhibition of PTEN and subsequently activation of PI3K/AKT/mTOR signaling pathway. Therefore, targeting circBIRC6 might represent a potential therapeutic strategy for improving bone loss in periodontitis.

miR‐27a‐5p alleviates periodontal inflammation by targeting phosphatase and tensin homolog deleted on chromosome ten

“…This conclusion is similar to that of the study by Lei et al on pancreatic acinar cells (Kong et al, 2019). However, some studies have suggested that PTEN is a protective factor against inflammation and ABL (Fu et al, 2019;Zhao et al, 2022) separately (Lee et al, 2018;Wei et al, 2020). However, Cao et al found that TNF-α expression was downregulated in PTEN −/− macrophages treated with LPS and concluded that PTEN is a negative regulator of Fc gamma receptors (FcγR) signaling, while a positive regulator of TLR4 signaling in the macrophage inflammatory response (Cao et al, 2004).…”

“…on pancreatic acinar cells (Kong et al., 2019). However, some studies have suggested that PTEN is a protective factor against inflammation and ABL (Fu et al., 2019; Zhao et al., 2022). A possible reason for this contradiction could be the dual role of PTEN in the macrophages.…”

Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

“…hDPSCs and hPDLSCs were isolated and cultured as previously described by the group. [46,47] Patients and Clinical Samples: The research protocol for reusing clinical specimens and medical information was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (IRB Number: 2022-056), and all procedures adhered to the Declaration of Helsinki guidelines. Written informed consent was obtained from all subjects.…”

Circular RNA hsa_circ_0084054 promotes the progression of periodontitis with diabetes via the miR‐508‐3p/PTEN axis

“…47 However, the circBIRC6/miR-543 axis regulates the osteogenic differentiation of PDLSCs through the PTEN/PI3K/AKT/mTOR signaling pathway, and silencing PTEN promotes the osteogenic differentiation of PDLSCs. 48 Moreover, when PTEN expression was decreased, PDLC apoptosis decreased, and cell proliferation was promoted. 49 The role of PTEN in periodontitis with diabetes has not been reported.…”

“…PTEN expression was reported to be reduced in a mouse model of periodontitis, and its deficiency activates IL‐1β and TNF‐α, which increases the number of osteoclasts and leads to alveolar bone loss 47 . However, the circBIRC6/miR‐543 axis regulates the osteogenic differentiation of PDLSCs through the PTEN/PI3K/AKT/mTOR signaling pathway, and silencing PTEN promotes the osteogenic differentiation of PDLSCs 48 . Moreover, when PTEN expression was decreased, PDLC apoptosis decreased, and cell proliferation was promoted 49 .…”