Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin
Jie Zhou, Yanlin Zhu, Dongqing Ai, Mengjiao Zhou, Han Li, Guangyue Li, Leilei Zheng, Jinlin Song
Abstract
Abstract Background Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N 6 -methyladenosine (m 6 A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m 6 A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m 6 A modification mechanism in diabetes-associated periodontitis. Methods Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M 6 A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining. Results Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m 6 A level in total RNA. FTO knockdown increased the m 6 A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m 6 A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling. Conclusions AGEs impaired BMSCs osteogenesis by regulating SOST in an m 6 A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.